Annals of Clinical and Experimental Hypertension

Podocytes as a therapeutic target

Review Article | Open Access

  • 1. Renal Electrolytes and Hypertension Division, University of Pennsylvania, USA
+ Show More - Show Less
Corresponding Authors
Deepak Nihalani, Renal Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, PA 19104, USA, Tel: 215-898-0192; Fax: 215-898-0189

A glomerulus is the filtration unit of a kidney where its primary function is to filter the blood and produce urine. The filtration apparatus of a glomerulus is composed of a three layered cellular assembly that consists of endothelial cells, GBM (glomerular basement membrane) and epithelial cells known as podocytes with their specialized junctions commonly known as the “slit diaphragm”, or the filtration slits. Injury to podocytes has been shown as a common denominator in various glomerular diseases leading to ESRD (end stage renal diseases) and renal failure. The podocytes have a unique architecture that is composed of a podocyte cell body and primary and tertiary processes that are critical for podocyte function. Podocytes lose their unique structure in the event of a glomerular injury, which is most often associated with podocyte actin cytoskeleton damage and podocytes detachment from the GBM leading to the loss of renal function. Studies over the past decade have established podocytes as a cell type critical for glomerular function, thus making them an ideal therapeutic target to develop therapies directed towards preserving glomerular filtration function. Recent studies have highlighted several cellular mechanisms and signaling targets such as suPAR, PLA2R, Rac1, Crk1/2, Trpc5, mTOR, Trpc6 and Notch that are involved in regulating podocyte function. More importantly, these studies have fueled the recent discoveries aimed at the identification and development of novel therapies or agents with the ability to preserve podocyte structure and function. The present review is an attempt to summarize the recent discoveries that have been made in the field of podocyte therapeutics and their impact on podocyte biology.


Arif E, Nihalani D (2013) Podocytes as a therapeutic target. Ann Clin Exp Hypertension 1(1): 1004.


•    Glomerulus
•    Podocyte injury
•    Signaling
•    Slit-diaphragm
•    Therapeutic targets


The filtration system of a kidney is critical for retaining essential proteins from the blood plasma and removal of toxic waste from the body. When a kidney loses its filtration function it results in life threatening complications and the survival usually depends on dialysis and eventually surgical intervention requiring a kidney transplant. The filtration function in a kidney is carried out by glomeruli and each glomerulus with its tubules is termed as a “nephron” which is also known as the filtration unit of the kidney [1]. A human kidney is composed of approximately 1 million glomeruli and on an average filters about 200 quarts of blood plasma generating about 2 quarts of urine per day [2]. The filtration function of a glomerulus is affected by a wide spectrum of diseases such as FSGS (focal and segmental glomerulosclerosis) and various nephrotic syndromes that are also the leading causes of end-stage renal disease (ESRD) [3-5]. The incidence of ESRD is increasing at an alarming rate and costs about $49 billion a year in patient care [6,7]. Limited progress has been made in the therapeutic advancement in this field primarily due to poor understanding of the basic mechanisms that regulate the different layers of the filtration assembly of the glomerulus.

The filtration barrier of a glomerulus is composed of three major cellular layers, the fenestrated endothelium, the intervening glomerular basement membrane (GBM) and podocytes, which collectively contribute towards the selective ultrafiltration of the blood plasma (Figure 1) [8,9]. This three layered structure facilitates the flow of plasma water and small solutes while restricting the flow of large plasma proteins such as albumin. Increased amount of albumin in the urine is the primary indication of a defective glomerular filtration barrier, a condition commonly known as “proteinuria” or “albuniuria”. Various glomerular diseases that induce proteinuria also demonstrate significant structural damage to podocytes [3,5,10]. These changes in podocytes have become the hallmark of proteinuria and serve as the diagnostic marker for various glomerular diseases [3,8]. This has also resulted in the worldwide acknowledgement of podocytes as the primary target for developing therapies against the existing glomerular diseases [11-13]. A significant effort is being made worldwide to understand the underlying mechanisms that regulate the structural and functional development of podocytes [14-16]. The past decade has seen a tremendous progress in the field of glomerular biology where a number of biomolecules and pathways have been uncovered that play a critical role in the maintenance of the filtration function of this filtration barrier [11,17,18] (Figure 1). Furthermore, it is critical that we understand the assembly and maintenance of this structure that will contribute towards designing novel therapies towards the prevention of this structure in the event of a glomerular injury (Figure 1).

Podocytes organization and the slit-diaphragm

The podocytes are highly specialized epithelial cells that consist of a cell body that branch off to give primary, secondary and tertiary processes. The tertiary processes also known as “foot processes” are attached to the GBM and extend as finger like projections that surround the glomerular capillary in an interdigitating fashion with the cell body facing the Bowman’s capsule and the urinary space [19]. The podocytes are highly polarized cells with apical or luminal and a basal cell membrane domain. The basal membrane, which contains the sole of foot process, is affixed to the GBM. The surface of the apical membrane is negatively charged because of its composition that contains sialoglycoproteins such as podoclyxin and podoendin [20]. Both apical and basal membranes are heterogeneous in nature with respect to their lipid composition [21,22]. Foot processes from different cell bodies interdigitate and the spaces between adjacent foot processes are connected via a thin membranous structure that is 40nm wide and is commonly known as the filtration slit or “slit-diaphragm” [3,5]. The unique structural organization of the slit diaphragm has been proposed to function as a permeability barrier, where it is freely permeable to water and small solutes and restricts the passage of large molecules such as albumin [3,23]. Several research findings reveal that proteins localized at the slit diaphragm play a critical role in maintaining the structure and function of podocytes [3,5,24]. Extensive research in this field has identified transmembrane proteins including Nephrin, Neph1, podocin, FAT and P-Cadherin that serves as the building blocks for this fascinating structure [3,5,10]. The cytoplasmic domains of Nephrin and Neph1 have been shown to serve as a structural link between the slit diaphragm and the actin cytoskeleton of podocytes and therefore were shown to participate in the signaling events that regulate the overall structure and function of podocytes [3,23]. Apart from these, several adapters, signaling and motor proteins including zona occludens-1 (ZO-1), CD2 adaptor protein (CD2AP), Nck, Crk 1, 2 and 3, Myo1c and Myo1e have also been identified that together contribute to the maintenance and integrity of the slit diaphragm [25-30]. Inactivation or genetic deletion of these proteins has been shown to induce structural alterations in podocytes leading to podocyte dysfunction and proteinuria in mice; more importantly, various glomerular diseases in humans have been shown to be linked to genetic mutations in many of these proteins [3,5,15,19,31], which further substantiates the role of these proteins in glomerular biology [23,32,33].

Podocyte injury

Podocyte injury is the common denominator in many forms of human and experimental glomerular diseases such as minimal change disease, focal segmental glomerulosclerosis (FSGS), membranous glomerulopathy, diabetic nephropathy (DN), and lupus nephritis [2,4]. Numerous studies now suggest that the injury to podocytes is the direct leading cause of glomerular disease development particularly in the case of FSGS [34-36]. Most notably, using various animal models it has been demonstrated that podocytes are the most vulnerable components of the glomerular tuft and that in majority of FSGS cases, it is the injury to podocytes that initiates the definitive pathologic sequence [37]. Podocytes are severely limited in their ability to repair themselves and are unable to replicate postnatally as suggested by the lack of an increase in podocyte cell number postnatally and during compensatory growth [34,38,39]. Data from the podocyte cell culture studies suggest that the differentiated podocytes are unable to proliferate, whereas undifferentiated or dedifferentiated podocytes from isolated glomeruli can proliferate [40-42]. An experimental animal model suggested that podocytes subjected to sustained mitogenic stimulation by FGF-2 [43] entered the cell cycle but were unable to reach the complete cell division, and resulted in bi- or multinucleated podocytes. Multinucleated podocytes were also observed in studies involving experimental [38,44] and human glumerulopathies [45-47]. Additionally, the loss of differentiated podocytes markers GLEPP1, synaptopodin, C3b-receptor and the transcription factor WT-1 expression was noted in these models [48]. These studies highlight the need for developing therapeutic alternatives that are directed towards preserving podocyte loss in the event of a glomerular injury.

Several studies of podocyte injury models note that early podocyte injury can be reversible where the actin cytoskeleton of podocytes has the ability to reorganize and restore the unique podocyte morphology [49-51]. Based on the nature of an injury, there are two models of podocyte injury, characterized as either chronic or acute; however, both lead to the loss of normal podocyte architecture and progression towards ESRD [50-52]. Additionally, there are different pathways including a dysregulated, inflammatory pathway, and a degenerative pathway that is proposed to function in podocyte injury [14,53]. In a dysregulated pathway that is commonly seen in the case of HIVassociated nephropathy, the dedifferentiation of podocytes leads to podocyte proliferation within Bowman’s space, collapsing of the glomerular tuft, GBM wrinkling and capillary loss [53,54]. The inflammatory pathway can lead to podocytes fixation to the parietal basement membrane followed by the establishment of tuft adhesions to Bowman’s capsule [53]. Further proliferation of podocytes and parietal cells results in the formation of cellular crescents and the healing of lesions by fibrosis results in segmental glomerulosclerosis [53]. In the case of degenerative form, which is most commonly observed, the persistent podocyte injury causes cell body attenuation, podocyte hypertrophy, and detachment from the GBM, and podocyte death leading to glomerulosclerosis and loss of renal function [53,54].

The Podocyte pathological lesion is also of common occurrence in other glomerular diseases such as inflammatory diseases (glomerulonephritis), immune-mediated diseases (membranous nephropathy, Heymann nephritis), mechanical stress (glomerular hypertension) and animal models of PAN (puromycin aminonucleoside) treatment. The Podocyte lesions may develop because of direct injury to podocytes, detachment of podocytes from the GBM or the damage of GBM [55,56]. Among the various animal models of podocyte injury developed over the years, the two models that have gained widespread recognition are the rat model of PAN injury where injury is induced by the administration of PAN and the protamine sulphate mouse model where podocyte damage occurs in response to the infusion of a highly cationic compound [26,49,57-59]. Importantly, these models have also been replicated in the podocyte cell culture system and thus have served as an excellent source to demonstrate cytoskeletal and molecular changes in podocytes and identify the various pathways that are affected during injury to podocytes [60-62].

An alternate mechanism of podocyte injury was noted in the study of integrins that play a central role in the attachment of podocytes to the GBM [63-65]. The antibodies directed against the antigens present in the basal podocyte cell membrane such as gp330 [66-68] or dipeptidylpeptidase IV [68] were shown to affect α3β1 integrin-fibronectin/laminin interactions leading to podocyte detachment from GBM and podocyte damage [37,65]. Furthermore, the genetic inactivation of α3 or β1 integrins was shown to induce severe disorganization of podocyte foot processes (FP) and loss of kidney function in newborn mice [69]. Damage to the GBM itself has been observed in various inflammatory and immune-mediated diseases where the injury is induced by reactive oxygen species (ROS) from neutrophils, monocytes/macrophages or resident glomerular cells that attack the GBM, or direct oxidation of GBM and by the activity of proteases that degrade the GBM or the connection of podocytes with the GBM [64,65,70-76]. Collectively, these studies highlight several mechanisms that contribute towards the podocyte injury and thus present multiple targets in podocytes that can be exploited therapeutically.

Molecular changes in an injured podocyte

The actin cytoskeleton of podocytes contributes towards the structural framework, unique morphology and maintaining the podocyte cell body and the function of podocytes. This actin cytoskeleton is divided into two major groups, the longitudinal actin microfilaments and the meshwork of actin filaments beneath the cell membrane [24,51,77]. The cytoskeleton of the primary podocyte FPs is composed of microtubules that in addition to providing structural support to the cell, anchors the intracellular molecules and impart the contraction and expansion abilities to the cells [23,24]. The FPs are also characterized by the cortical network of short branched actin filaments and the presence of highly ordered parallel, contractile actin filament bundles, which are thought to modulate the permeability of the filtration barrier through changes in foot process morphology [24,51,77]. Apart from the structural stability the actin cytoskeleton plays a major role in cell signaling and the intracellular organization of podocyte proteins [15,32,51,52]. The disorganization of this well characterized podocyte actin cytoskeleton is a major event evidenced during podocyte injury [11,51,52,78]. These changes often lead to flattening of podocytes that is commonly referred to as “podocyte effacement” and loss of the slit diaphragm [14,26,37]. Over the years several actin associated proteins including actinin-4 and synaptopodin that regulate the dynamics of actin cytoskeleton have been investigated. Genetic mutations of Alpha-Actinin-4 in human and knockout or over expression have been associated with the development of glomerular diseases leading to proteinuria [79-81]. Analysis of synaptopodin-null mice showed that these mice were resistant to protamine sulfate induced foot process effacement synaptopodin suggesting a critical role for synaptopodin in podocyte biology [81]. Additionally, actin based molecular motors such as Myo1c and Myo1e that are associated with protein trafficking has been recently investigated for their role in podocyte development, maintenance and glomerular function [25,29,82,83]. Growth factor receptors such as vascular endothelial growth factor [84,85] and transforming growth factor β [70], GPCRs such as the angiotensin type 1 receptor (AT1R) [86,87], signaling through Notch [88,71] or integrins [89-92], TRPC ion channels such [93,72,73], suPAR [74], PLA2R [94] and many other molecules have been identified for their role in podocyte injury.

The increasing evidence now overwhelmingly suggests that maintaining a healthy actin cytoskeleton is central to podocyte maintenance and function and therefore, targeting the well being of podocyte actin cytoskeleton is a reasonable therapeutic approach to prevent podocyte function in the event of a glomerular injury.

Podocytes as therapeutic target

With the growing incidences of glomerular diseases worldwide, there is an urgent need for better therapies that are directed towards preserving podocyte function and reduce the morbidity and mortality rates associated with renal failure. Recent advancements in the drug therapy field has led to the identification of many drugs including glucocorticosteroids and calcineurin antagonists with observed potent protective effects; however, the nonspecific nature of these drugs with undesirable systemic adverse effects severely limits their potential use and suggests the need for further research to uncover novel therapeutic alternatives to prevent podocyte damage [11]. Among the podocyte targets, angiotensin inhibition has gained significant attention due to its ability to prevent the development of glomerulosclerosis in animal and cell culture models [95,96,75]. The soluble form of the urokinase plasminogen-activator receptor (suPAR) that was earlier investigated for its possible role in cell motility, invasion and metastasis was recently characterized as the FSGS inducing factor and was shown to be elevated in the FSGS patients [74,97]. This finding has galvanized the podocyte community and has led to the designing of therapies directed towards lowering the suPAR levels in blood plasma [74,97].

Among the other pathways, the transmembrane receptor, M-type phospholipase A2 receptor (PLA2R), has been identified as a target antigen in membranous nephropathy [76,98] The glomerular PLA2R expression was elevated in the MN patients that contained increased anti-PLA2R antibody levels as compared to the MN patients without detectable anti-PLA2R antibodies or patients with other types of glomerular diseases [99]. The PLA2R expression can be assessed in kidney biopsies and differentiates patients with MN caused due to anti-PLA2R antibodies from those with secondary forms of MN. The Rituximab-Induced depletion of Anti-PLA2 R autoantibodies has emerged as a promising therapy for MN patients; however, some patients entered into remission following this therapy [100], which further suggests that further investment should be made in understanding the pathogenesis of this disease and designing alternate therapies.

Molecular targets in podocytes

It is of no big surprise that many investigators are recognizing the potential of podocytes as therapeutic targets and are targeting pathways specifically within the podocytes to develop therapies for preserving glomerular filtration function. Some of the most promising strategies include targeting the B7 protein and the TRPC (transient receptor potential) channels [93,101]. A recent study suggested that the expression of B7-1 (CD-80) protein was elevated in certain glomerular disease conditions [101]. The B7-1 promotes disease-associated podocyte migration through inactivation of β1 integrin and hence the B7-1–positive podocytes demonstrate reduced ability to attach to the surrounding matrix through β1 integrin. The increased B7-1 protein expression is associated with increased podocyte migration, which serves as a marker for podocyte effacement and proteinuria [101]. Remarkably, Abatacept (CTLA-4–Ig) a known inhibitor of the T-cell co-stimulatory molecule CD80 appears to cure the nephrotic syndrome patients that were shown to contain increased levels of B7-1 protein [101].

The other major pathway that recently gained significant attention for its therapeutic value involves TRP channels. The TRP channels are highly conserved nonselective cationic channels, and play a major role in chemo and mechanosensation [93,101]. The TRPC6 channel was shown to be a functional component of podocytes where it was investigated for its interaction with scaffolding molecules, signaling proteins, cytoskeletal elements, and many ion channels such as Ca2+-activated K+ channels (BKCa channels) [93,101]. Alteration in the function of this ion channel was shown to be associated with podocyte damage suggesting its role in maintaining glomerular function [93,102,103]. Moreover, gain of function mutations in TRPC6 in humans or the overexpression of the wild-type TRPC6 protein in mice both induced renal damage [104,105]. Although TRPC6 is expressed in many cells types but mutation of TRPC6 primarily demonstrated FSGS like symptoms and did not produce any other pathological phenotype [106]. This unique glomerular phenotype suggests the exceptional role of TRPC6 in podocytes that may regulate subtle changes in Ca2+ dynamics and actin cytoskeleton [106,107]. These studies have led to multiple experimental hypotheses, which focus on modifying TRPC6 expression or blocking TRPC6 channels using specific inhibitors as potential therapeutic strategies [90,107]. Another TRP channel, the TRPC5 that is highly expressed in brain and kidney was recently shown to be an essential component of the glomerular filtration system [108,109]. The TRPC5 and TRPC6 channels act as antagonistic regulators of actin remodeling and cell motility in fibroblasts and kidney podocytes [72]. Recent study revealed that loss of TRPC5 in mice or the pharmacological inhibition of TRPC5 by a small molecule inhibitor prevented the activation of small GTP binding protein Rac 1 and stabilized Synaptopodin and protected mice from albuminuria [109].

Cell signaling as a potential target in podocyte

The Rho-family small GTPase including RhoA and Rac1 are associated with cellular signaling, cell migration and inflammation in a variety of cell types [110,111]. Activation of these molecules has been associated with podocyte injury and proteinuric kidney disease [110,111]. The role of small GTPases has been implicated in dynamic shape changes seen in podocytes during development and in disease states [51]. The GTPase Cdc42 has been shown to play a role in the podocyte development, whereas, RhoA and Rac1 GTPases are seems to be involved in post development stages of podocyte maintenance [112]. The Activation of RhoA or the overexpression of dominant negative RhoA resulted in foot process effacement and proteinuria [113,114]. In contrast, the podocyte-specific loss of Rac1 protected mice from the glomerular injury induced by protamine sulfate infusion [115]. Further the rac1 inhibitors were found to inhibit the increased Rac1 and CDC42 dependent cell migration observed in steroid resistant nephrotic syndrome (NS) [116]. Additionally, the podocyte-specific, inducible transgenic mice expressing constitutively active Rac1 lead to the rapid onset of proteinuria and foot process effacement [112]. Collectively, these findings provide ample evidence for the role of GTPases in regulating podocyte structure and function and thus modulating their function has become a novel approach in developing therapies for the treatment of chronic kidney diseases [112].

A recent report highlighted the role of another signaling protein Crk and its family members (Crk1/2 and CrkL) that were shown to interact with the slit diaphragm protein nephrin [26,32]. Crk plays a pivotal role in transducing signals that regulate actin cytoskeletal dynamics, cell spreading, and motility by mobilizing and activating Rho family of small GTPases, [117- 119]. Crk-mediated signaling can be initiated by a variety of stimuli including growth factors, cytokines, or integrin-mediated cell adhesion, and is involved in cell proliferation, differentiation, and cell motility [119]. Interestingly, the podocyte specific deletion of Crk1/2 in mice prevented foot process effacement in a podocyte injury model where the injury was induced by the infusion of protamine sulfate [26]. It is notable that Crk mediates its function through FAK (focal adhesion kinase) and Cas protein complex which were also hyper-phosphorylated in the glomeruli of minimal change disease and membranous nephropathy patients [26]. This study was remarkable in the sense that it provided FAK as a novel therapeutic target in podocytes [26]. Indeed, genetic and pharmacological inactivation of FAK was shown to attenuate the foot process effacement and proteinuria in various diseased models [120]. Although these studies have shown promising targets for preventing podocyte damage in response to glomerular injury, they may only target a subset of glomerular diseases [26]. Therefore, future studies should be considered to evaluate such inhibitors in specific susceptible subsets of human glomerulopathy in which podocyte FAK and Cas are phosphorylated.

Activation of Notch pathway plays critical role in the development of a kidney and the pathogenesis of glomerular diseases [71,121]. Four Notch receptors exist in mammals that are activated upon the binding of ligands such as Delta-like1, 3, and 4, and Jagged 1 and 2 leading to a series of proteolytic steps initiated by presenilin-dependent gamma secretase-like protease [122]. This results in the release of Notch intracellular (IC) domain, which ultimately translocates to the nucleus and binds RBP-jk transcription factor and activate the expression of Notch effector protein [122,123]. While Notch signaling is required during nephrogenesis, its suppression is necessary for differentiation [124-127]. The upregulation of Notch signaling has been identified in many kidney diseases including inflammation and fibrosis, and during glomerular injuries such as immunodeficiency virus-associated nephropathy (HIVAN) [121,122,128,129]. It was further established that the activation of Notch pathway specifically in podocytes was sufficient to induce podocyte loss and glomerular failure. In contrast, the genetic ablation of Notch pathway resulted in resistance to podocyte apoptosis and albuminuria [71]. Interestingly, γ-secretase inhibitors also prevented disease onset in a toxic podocyte damage model, further supporting Notch signaling as a therapeutic target for preventing podocyte damage [130].

The mammalian target of rapamycin (mTOR) is a serine/ threonine kinase of the phosphoinositide 3-kinase (PI3K)-related kinase family that contains two distinct complexes, mTORC1 and mTORC2. Rapamycin is a fungal metabolite that is known for its potent growth-inhibitory and immunosuppressant functions [131,132]. The mTORC1 is mainly involved in regulating cell cycle progression, translational control, and cellular energy responses [133], whereas mTORC2 was identified as the kinase responsible for phosphorylating Akt and plays a major role in regulating actin cytoskeleton [134,135]. Role of mTOR has been investigated in various human diseases including cancer, diabetes, neurodegenerative disorders, and polycystic kidney disease [136,137]. Recent investigations revealed that inhibition of mTORC1 by rapamycin or everolimus can favorably modify glomerular diseases, such as minimal change disease [138], focal segmental glomerulosclerosis [139], membranous nephropathy [140,141], crescentic glomerulonephritis [142], and diabetic nephropathy [143]. Studies also suggest that mTOR inhibiton can protect and prevent podocytes from progressive diabetic nephropathy [144]. In diabetic animals, rapamycin prevented GBM thickening, glomerular hypertrophy, mesangial expansion, and renal macrophage [143]. Despite the protective effect of rapamycin in animal models the use of rapamycin therapy in human patients has been limited due to a varied human response possible due to off-target effects of rapamycin [145]. This further suggests a need for better in-depth understanding of this pathway and its functional role in various glomerular diseases. Nevertheless, development of drugs that have the potential to modify this pathway will be promising future therapeutic candidates for the treatment of glomerular diseases.

It is remarkable, yet baffling that the proteins that are so essential for podocyte function, their loss (rather than being detrimental for podocyte function), protects podocytes from injury [26,101,109,112] (Figure 1). There are two possible hypothetical explanations for such occurrence; either the protein loss has a differential response based on the nature of the glomerular disease and thus may offer protection in one model but may aggravate disease in other models or the loss of protein shuts of the signaling pathway that is involved in the injury response and thus rendering the cell unresponsive to the injury stimulus. Genetic deletion of Rac1 provides support for the first hypothesis since it showed protective effect in the protamine sulphate injury model and had aggravated injury response in the long-term model of chronic hypertensive glomerular damage [112]. Since these signaling proteins mediate a broad range of biological processes and are involved in numerous pathways, further studies are necessary to identify additional downstream or upstream signaling targets that will aid in designing specific and highly effective therapies for restoring glomerular function during renal injury.


Preventing podpocyte damage will prevent glomerular injury and preserve renal function, is soon becoming the mantra of the podocyte biologists. This is largely due to our increased understanding of the podocyte biology in the last decade. Additionally this has significantly contributed towards the identification of molecular targets with applications in glomerular disease prevention and progression. Understanding of the signaling pathways in podocytes have taught us that podocytes are regulated through complex set of mechanisms and therefore, therapeutic advancement in the field of podocyte biology will require multiple approaches to identify multiple targets and develop combinatorial therapies to prevent podocyte damage and thus preserve renal function. With the increasing knowledge of the molecular composition of podocytes, the investigators in the field of podocyte biology are uniquely positioned to identify several druggable targets that will aid in the development of therapies directed towards preventing podocytopathy.


NephCure Foundation (NCF), NephCure Postdoctoral Grants 2012-RFP-001 to E. A., National Institutes of Health, NIDDK, Grant RO1 1R01DK087956 to D. N. are duly acknowledged.


1. Tryggvason K. Unraveling the mechanisms of glomerular ultrafiltration: nephrin, a key component of the slit diaphragm. J Am Soc Nephrol. 1999; 10: 2440-2445.

2. Basgen JM, Steffes MW, Stillman AE, Mauer SM. Estimating glomerular number in situ using magnetic resonance imaging and biopsy. Kidney Int. 1994; 45: 1668-1672.

3. Tryggvason K, Patrakka J, Wartiovaara J. Hereditary proteinuria syndromes and mechanisms of proteinuria. N Engl J Med. 2006; 354: 1387-1401.

4. Shankland SJ. The podocyte’s response to injury: role in proteinuria and glomerulosclerosis. Kidney Int. 2006; 69: 2131-2147.

5. Pavenstädt H, Kriz W, Kretzler M. Cell biology of the glomerular podocyte. Physiol Rev. 2003; 83: 253-307.

6. Nolan CR. Strategies for improving long-term survival in patients with ESRD. J Am Soc Nephrol. 2005; 16 Suppl 2: S120-127.

7. United States Renal Data System, h. w. u. o. 2013.

8. Brenner BM, Hostetter TH, Humes HD. Molecular basis of proteinuria of glomerular origin. N Engl J Med. 1978; 298: 826-833.

9. Rennke HG, Venkatachalam MA. Glomerular permeability of macromolecules. Effect of molecular configuration on the fractional clearance of uncharged dextran and neutral horseradish peroxidase in the rat. J Clin Invest. 1979; 63: 713-717.

10. Haraldsson B, Nyström J, Deen WM. Properties of the glomerular barrier and mechanisms of proteinuria. Physiol Rev. 2008; 88: 451- 487.

11. Mathieson PW. The podocyte as a target for therapies--new and old. Nat Rev Nephrol. 2011; 8: 52-56.

12. Leeuwis JW, Nguyen TQ, Dendooven A, Kok RJ, Goldschmeding R. Targeting podocyte-associated diseases. Adv Drug Deliv Rev. 2010; 62: 1325-1336.

13. Reiser J, Sever S. Podocyte biology and pathogenesis of kidney disease. Annu Rev Med. 2013; 64: 357-366.

14. Greka A, Mundel P. Cell biology and pathology of podocytes. Annu Rev Physiol. 2012; 74: 299-323.

15. George B, Holzman LB. Signaling from the podocyte intercellular junction to the actin cytoskeleton. Semin Nephrol. 2012; 32: 307-318.

16. Johnstone DB, Holzman LB. Clinical impact of research on the podocyte slit diaphragm. Nat Clin Pract Nephrol. 2006; 2: 271-282.

17. Dessapt-Baradez C, Woolf AS, White KE, Pan J, Huang JL, Hayward AA, et al. Targeted Glomerular Angiopoietin-1 Therapy for Early Diabetic Kidney Disease. J Am Soc Nephrol. 2013.

18. D’Agati VD, Kaskel FJ, Falk RJ. Focal segmental glomerulosclerosis. N Engl J Med. 2011; 365: 2398-2411.

19. Haraldsson B, Jeansson M. Glomerular filtration barrier. Curr Opin Nephrol Hypertens. 2009; 18: 331-335.

20. Huang TW, Langlois JC. Podoendin. A new cell surface protein of the podocyte and endothelium. J Exp Med. 1985; 162: 245-267.

21. Haraldsson B, Nyström J. The glomerular endothelium: new insights on function and structure. Curr Opin Nephrol Hypertens. 2012; 21: 258-263.

22. Schwarz K, Simons M, Reiser J, Saleem MA, Faul C, Kriz W, et al. Podocin, a raft-associated component of the glomerular slit diaphragm, interacts with CD2AP and nephrin. J Clin Invest. 2001; 108: 1621-1629.

23. Tryggvason K, Pikkarainen T, Patrakka J. Nck links nephrin to actin in kidney podocytes. Cell. 2006; 125: 221-224.

24. Marshall SM. The podocyte: a potential therapeutic target in diabetic nephropathy? Curr Pharm Des. 2007; 13: 2713-2720.

25. Arif E, Wagner MC, Johnstone DB, Wong HN, George B, Pruthi PA, et al. Motor protein Myo1c is a podocyte protein that facilitates the transport of slit diaphragm protein Neph1 to the podocyte membrane. Mol Cell Biol. 2011; 31: 2134-2150.

26. George B, Verma R, Soofi AA, Garg P, Zhang J, Park TJ, et al. Crk1/2- dependent signaling is necessary for podocyte foot process spreading in mouse models of glomerular disease. J Clin Invest. 2012; 122: 674- 692.

27. Huber TB, Benzing T. The slit diaphragm: a signaling platform to regulate podocyte function. Curr Opin Nephrol Hypertens. 2005; 14: 211-216.

28. Jones N, Blasutig IM, Eremina V, Ruston JM, Bladt F, Li H, et al. Nck adaptor proteins link nephrin to the actin cytoskeleton of kidney podocytes. Nature. 2006; 440: 818-823.

29. Krendel M, Kim SV, Willinger T, Wang T, Kashgarian M, Flavell RA, et al. Disruption of Myosin 1e promotes podocyte injury. J Am Soc Nephrol. 2009; 20: 86-94.

30. Patrakka J, Tryggvason K. Nephrin--a unique structural and signaling protein of the kidney filter. Trends Mol Med. 2007; 13: 396-403.

31. McKnight AJ, Currie D, Maxwell AP. Unravelling the genetic basis of renal diseases; from single gene to multifactorial disorders. J Pathol. 2010; 220: 198-216.

32. Verma R, Kovari I, Soofi A, Nihalani D, Patrie K, Holzman LB. Nephrin ectodomain engagement results in Src kinase activation, nephrin phosphorylation, Nck recruitment, and actin polymerization. J Clin Invest. 2006; 116: 1346-1359.

33. Shih NY, Li J, Cotran R, Mundel P, Miner JH, Shaw AS. CD2AP localizes to the slit diaphragm and binds to nephrin via a novel C-terminal domain. Am J Pathol. 2001; 159: 2303-2308.

34. Fries JW, Sandstrom DJ, Meyer TW, Rennke HG. Glomerular hypertrophy and epithelial cell injury modulate progressive glomerulosclerosis in the rat. Lab Invest. 1989; 60: 205-218.

35. Asanuma K, Mundel P. The role of podocytes in glomerular pathobiology. Clin Exp Nephrol. 2003; 7: 255-259.

36. Kriz W. Podocyte is the major culprit accounting for the progression of chronic renal disease. Microsc Res Tech. 2002; 57: 189-195.

37. Kriz W, Gretz N, Lemley KV. Progression of glomerular diseases: is the podocyte the culprit? Kidney Int. 1998; 54: 687-697.

38. Nagata M, Kriz W. Glomerular damage after uninephrectomy in young rats. II. Mechanical stress on podocytes as a pathway to sclerosis. Kidney Int. 1992; 42: 148-160.

39. Pabst R, Sterzel RB. Cell renewal of glomerular cell types in normal rats. An autoradiographic analysis. Kidney Int. 1983; 24: 626-631.

40. Mundel P, Kriz W. Cell culture of podocytes. Exp Nephrol. 1996; 4: 263-266.

41. Mundel P, Reiser J, Kriz W. Induction of differentiation in cultured rat and human podocytes. J Am Soc Nephrol. 1997; 8: 697-705.

42. Mundel P, Reiser J, Zúñiga Mejía Borja A, Pavenstädt H, Davidson GR, Kriz W, et al. Rearrangements of the cytoskeleton and cell contacts induce process formation during differentiation of conditionally immortalized mouse podocyte cell lines. Exp Cell Res. 1997; 236: 248- 58.

43. Kriz W, Hähnel B, Rösener S, Elger M. Long-term treatment of rats with FGF-2 results in focal segmental glomerulosclerosis. Kidney Int. 1995; 48: 1435-1450.

44. Tenschert S, Elger M, Lemley KV. Glomerular hypertrophy after subtotal nephrectomy: relationship to early glomerular injury. Virchows Arch. 1995; 426: 509-517.

45. Chandra M, Stokes MB, Kaskel F. Multinucleated podocytes: a diagnostic clue to cystinosis. Kidney Int. 2010; 78: 1052.

46. Schwartz MM, Lewis EJ. Focal segmental glomerular sclerosis: the cellular lesion. Kidney Int. 1985; 28: 968-974.

47. Nagata M, Yamaguchi Y, Komatsu Y, Ito K. Mitosis and the presence of binucleate cells among glomerular podocytes in diseased human kidneys. Nephron. 1995; 70: 68-71.

48. Barisoni L, Kriz W, Mundel P, D’Agati V. The dysregulated podocyte phenotype: a novel concept in the pathogenesis of collapsing idiopathic focal segmental glomerulosclerosis and HIV-associated nephropathy. J Am Soc Nephrol. 1999; 10: 51-61.

49. Wagner MC, Rhodes G, Wang E, Pruthi V, Arif E, Saleem MA, et al. Ischemic injury to kidney induces glomerular podocyte effacement and dissociation of slit diaphragm proteins Neph1 and ZO-1. J Biol Chem. 2008; 283: 35579-35589.

50. Mathieson PW. Podocyte actin in health, disease and treatment. Nephrol Dial Transplant. 2010; 25: 1772-1773.

51. Faul C, Asanuma K, Yanagida-Asanuma E, Kim K, Mundel P. Actin up: regulation of podocyte structure and function by components of the actin cytoskeleton. Trends Cell Biol. 2007; 17: 428-437.

52. Welsh GI, Saleem MA. The podocyte cytoskeleton--key to a functioning glomerulus in health and disease. Nat Rev Nephrol. 2011; 8: 14-21.

53. Kriz W, LeHir M. Pathways to nephron loss starting from glomerular diseases-insights from animal models. Kidney Int. 2005; 67: 404-419.

54. Mundel P, Shankland SJ. Podocyte biology and response to injury. J Am Soc Nephrol. 2002; 13: 3005-3015.

55. Kerjaschki D. Dysfunctions of cell biological mechanisms of visceral epithelial cell (podocytes) in glomerular diseases. Kidney Int. 1994; 45: 300-313.

56. Diamond JR. The role of reactive oxygen species in animal models of glomerular disease. Am J Kidney Dis. 1992; 19: 292-300.

57. Bertram JF, Messina A, Ryan GB. In vitro effects of puromycin aminonucleoside on the ultrastructure of rat glomerular podocytes. Cell Tissue Res. 1990; 260: 555-563.

58. Seiler MW, Rennke HG, Venkatachalam MA, Cotran RS. Pathogenesis of polycation-induced alterations (“fusion”) of glomerular epithelium. Lab Invest. 1977; 36: 48-61.

59. Seiler MW, Venkatachalam MA, Cotran RS. Glomerular epithelium: structural alterations induced by polycations. Science. 1975; 189: 390-393.

60. Kanjanabuch T, Ma LJ, Chen J, Pozzi A, Guan Y, Mundel P, et al. PPARgamma agonist protects podocytes from injury. Kidney Int. 2007; 71: 1232-1239.

61. Vega-Warner V, Ransom RF, Vincent AM, Brosius FC, Smoyer WE. Induction of antioxidant enzymes in murine podocytes precedes injury by puromycin aminonucleoside. Kidney Int. 2004; 66: 1881- 1889.

62. Reiser J, Pixley FJ, Hug A, Kriz W, Smoyer WE, Stanley ER, et al. Regulation of mouse podocyte process dynamics by protein tyrosine phosphatases rapid communication. Kidney Int. 2000; 57: 2035-2042.

63. Kerjaschki D, Ojha PP, Susani M, Horvat R, Binder S, Hovorka A, et al. A beta 1-integrin receptor for fibronectin in human kidney glomeruli. Am J Pathol. 1989; 134: 481-489.

64. Korhonen M, Ylänne J, Laitinen L, Virtanen I. The alpha 1-alpha 6 subunits of integrins are characteristically expressed in distinct segments of developing and adult human nephron. J Cell Biol. 1990; 111: 1245-1254.

65. kretzler M. Regulation of adhesive interaction between podocytes and glomerular basement membrane. Microsc Res Tech. 2002; 57: 247-253.

66. Kerjaschki D, Neale TJ. Molecular mechanisms of glomerular injury in rat experimental membranous nephropathy (Heymann nephritis) J Am Soc Nephrol. 1996; 7: 2518-2526.

67. Kerjaschki D. Epitopes and radicals: early events in glomerular injury in membranous nephropathy. Exp Nephrol. 1995; 3: 1-8.

68. Van Leer EH, Ronco P, Verroust P, van der Wal AM, Hoedemaeker PJ, De Heer E. Epitope specificity of anti-gp330 autoantibodies determines the development of proteinuria in active Heymann nephritis. Am J Pathol. 1993; 142: 821-829.

69. Kreidberg JA, Symons JM. Integrins in kidney development, function, and disease. Am J Physiol Renal Physiol. 2000; 279: F233-242.

70. Böttinger EP, Bitzer M. TGF-beta signaling in renal disease. J Am Soc Nephrol. 2002; 13: 2600-2610.

71. Niranjan T, Bielesz B, Gruenwald A, Ponda MP, Kopp JB, Thomas DB, et al. The Notch pathway in podocytes plays a role in the development of glomerular disease. Nat Med. 2008; 14: 290-298.

72. Tian D, Jacobo SM, Billing D, Rozkalne A, Gage SD, Anagnostou T, et al. Antagonistic regulation of actin dynamics and cell motility by TRPC5 and TRPC6 channels. Sci Signal. 2010; 3: ra77.

73. Eckel J, Lavin PJ, Finch EA, Mukerji N, Burch J, Gbadegesin R, et al. TRPC6 enhances angiotensin II-induced albuminuria. J Am Soc Nephrol. 2011; 22: 526-535.

74. Wei C, El Hindi S, Li J, Fornoni A, Goes N, Sageshima J, et al. Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis. Nat Med. 2011; 17: 952-60.

75. Yu L, Lin Q, Feng J, Dong X, Chen W, Liu Q, et al. Inhibition of nephrin activation by c-mip through Csk-Cbp-Fyn axis plays a critical role in Angiotensin II-induced podocyte damage. Cell Signal. 2013; 25: 581- 588.

76. Beck LH Jr, Bonegio RG, Lambeau G, Beck DM, Powell DW, Cummins TD, et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med. 2009; 361: 11-21.

77. Drenckhahn D, Franke RP. Ultrastructural organization of contractile and cytoskeletal proteins in glomerular podocytes of chicken, rat, and man. Lab Invest. 1988; 59: 673-682.

78. Barisoni L, Mundel P. Podocyte biology and the emerging understanding of podocyte diseases. Am J Nephrol. 2003; 23: 353-360.

79. Smoyer WE, Mundel P, Gupta A, Welsh MJ. Podocyte alpha-actinin induction precedes foot process effacement in experimental nephrotic syndrome. Am J Physiol. 1997; 273: F150-157.

80. Kos CH, Le TC, Sinha S, Henderson JM, Kim SH, Sugimoto H, et al. Mice deficient in alpha-actinin-4 have severe glomerular disease. J Clin Invest. 2003; 111: 1683-1690.

81. Michaud JL, Lemieux LI, Dubé M, Vanderhyden BC, Robertson SJ, Kennedy CR. Focal and segmental glomerulosclerosis in mice with podocyte-specific expression of mutant alpha-actinin-4. J Am Soc Nephrol. 2003; 14: 1200-1211.

82. Arif E, Kumari B, Wagner MC, Zhou W, Holzman LB, Nihalani D. Myo1c is an unconventional myosin required for zebrafish glomerular development. Kidney Int. 2013; 84: 1154-1165.

83. Bi J, Chase SE, Pellenz CD, Kurihara H, Fanning AS, Krendel M. Myosin 1e is a component of the glomerular slit diaphragm complex that regulates actin reorganization during cell-cell contact formation in podocytes. Am J Physiol Renal Physiol. 2013; 305: 532-44.

84. Eremina V, Sood M, Haigh J, Nagy A, Lajoie G, Ferrara N, et al. Glomerularspecific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases. J Clin Invest. 2003; 111: 707-16.

85. Eremina V, Jefferson JA, Kowalewska J, Hochster H, Haas M, Weisstuch J, et al. VEGF inhibition and renal thrombotic microangiopathy. N Engl J Med. 2008; 358: 1129-1136.

86. Hoffmann S, Podlich D, Hähnel B, Kriz W, Gretz N. Angiotensin II type 1 receptor overexpression in podocytes induces glomerulosclerosis in transgenic rats. J Am Soc Nephrol. 2004; 15: 1475-1487.

87. Gloy J, Henger A, Fischer KG, Nitschke R, Mundel P, Bleich M, et al. Angiotensin II depolarizes podocytes in the intact glomerulus of the Rat. J Clin Invest. 1997; 99: 2772-2781.

88. Waters AM, Wu MY, Onay T, Scutaru J, Liu J, Lobe CG, et al. Ectopic notch activation in developing podocytes causes glomerulosclerosis. J Am Soc Nephrol. 2008; 19: 1139-1157.

89. Kreidberg JA, Donovan MJ, Goldstein SL, Rennke H, Shepherd K, Jones RC, et al. Alpha 3 beta 1 integrin has a crucial role in kidney and lung organogenesis. Development. 1996; 122: 3537-3547.

90. Kanasaki K, Kanda Y, Palmsten K, Tanjore H, Lee SB, Lebleu VS, et al. Integrin beta1-mediated matrix assembly and signaling are critical for the normal development and function of the kidney glomerulus. Dev Biol. 2008; 313: 584-593.

91. reidberg JA. Functions of alpha3beta1 integrin. Curr Opin Cell Biol. 2000; 12: 548-553.

92. Clement LC, Avila-Casado C, Macé C, Soria E, Bakker WW, Kersten S, et al. Podocyte-secreted angiopoietin-like-4 mediates proteinuria in glucocorticoid-sensitive nephrotic syndrome. Nat Med. 2011; 17: 117- 122.

93. Reiser J, Polu KR, Möller CC, Kenlan P, Altintas MM, Wei C, et al. TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function. Nat Genet. 2005; 37: 739-744.

94. Stanescu HC, Arcos-Burgos M, Medlar A, Bockenhauer D, Kottgen A, Dragomirescu L, et al. Risk HLA-DQA1 and PLA(2)R1 alleles in idiopathic membranous nephropathy. N Engl J Med. 2011; 364: 616- 626.

95. Kumar R, Boim MA. Diversity of pathways for intracellular angiotensin II synthesis. Curr Opin Nephrol Hypertens. 2009; 18: 33-39.

96. Matsusaka T, Asano T, Niimura F, Kinomura M, Shimizu A, Shintani A, et al. Angiotensin receptor blocker protection against podocyte-induced sclerosis is podocyte angiotensin II type 1 receptor-independent. Hypertension. 2010; 55: 967-73.

97. Reiser J, Wei C, Tumlin J. Soluble urokinase receptor and focal segmental glomerulosclerosis. Curr Opin Nephrol Hypertens. 2012; 21: 428-432.

98. Qin W, Beck LH Jr, Zeng C, Chen Z, Li S, Zuo K, et al. Anti-phospholipase A2 receptor antibody in membranous nephropathy. J Am Soc Nephrol. 2011; 22: 1137-1143.

99. Hoxha E, Kneißler U, Stege G, Zahner G, Thiele I, Panzer U, et al. Enhanced expression of the M-type phospholipase A2 receptor in glomeruli correlates with serum receptor antibodies in primary membranous nephropathy. Kidney Int. 2012; 82: 797-804.

100. Beck LH Jr, Fervenza FC, Beck DM, Bonegio RG, Malik FA, Erickson SB, et al. Rituximab-induced depletion of anti-PLA2R autoantibodies predicts response in membranous nephropathy. J Am Soc Nephrol. 2011; 22: 1543-1550.

101. Yu CC, Fornoni A, Weins A, Hakroush S, Maiguel D, Sageshima J, et al. Abatacept in B7-1-Positive Proteinuric Kidney Disease. N Engl J Med. 2013.

102. Winn MP, Daskalakis N, Spurney RF, Middleton JP. Unexpected role of TRPC6 channel in familial nephrotic syndrome: does it have clinical implications? J Am Soc Nephrol. 2006; 17: 378-387.

103. Greka A, Mundel P. Balancing calcium signals through TRPC5 and TRPC6 in podocytes. J Am Soc Nephrol. 2011; 22: 1969-1980.

104. Möller CC, Wei C, Altintas MM, Li J, Greka A, Ohse T, et al. Induction of TRPC6 channel in acquired forms of proteinuric kidney disease. J Am Soc Nephrol. 2007; 18: 29-36.

105. Krall P, Canales CP, Kairath P, Carmona-Mora P, Molina J, Carpio JD, et al. Podocyte-specific overexpression of wild type or mutant trpc6 in mice is sufficient to cause glomerular disease. PLoS One. 2010; 5: e12859.

106. Dryer SE, Reiser J. TRPC6 channels and their binding partners in podocytes: role in glomerular filtration and pathophysiology. Am J Physiol Renal Physiol. 2010; 299: F689-701.

107. Sever S, Altintas MM, Nankoe SR, Möller CC, Ko D, Wei C, et al. Proteolytic processing of dynamin by cytoplasmic cathepsin L is a mechanism for proteinuric kidney disease. J Clin Invest. 2007; 117: 2095-2104.

108. Latorre R, Brauchi S, Orta G, Zaelzer C, Vargas G. ThermoTRP channels as modular proteins with allosteric gating. Cell Calcium. 2007; 42: 427-438.

109. Schaldecker T, Kim S, Tarabanis C, Tian D, Hakroush S, Castonguay P, et al. Inhibition of the TRPC5 ion channel protects the kidney filter. J Clin Invest. 2013; 123: 5298-5309.

110. Babelova A, Jansen F, Sander K, Löhn M, Schäfer L, Fork C, et al. Activation of Rac-1 and RhoA Contributes to Podocyte Injury in Chronic Kidney Disease. PLoS One. 2013; 8: e80328.

111. Asanuma K, Yanagida-Asanuma E, Faul C, Tomino Y, Kim K, Mundel P. Synaptopodin orchestrates actin organization and cell motility via regulation of RhoA signalling. Nat Cell Biol. 2006; 8: 485-491.

112. Yu H, Suleiman H, Kim AH, Miner JH, Dani A, Shaw AS, et al. Rac1 activation in podocytes induces rapid foot process effacement and proteinuria. Mol Cell Biol. 2013; 33: 4755-4764.

113. Wang L, Ellis MJ, Gomez JA, Eisner W, Fennell W, Howell DN, et al. Mechanisms of the proteinuria induced by Rho GTPases. Kidney Int. 2012; 81: 1075-1085.

114. Zhu L, Jiang R, Aoudjit L, Jones N, Takano T. Activation of RhoA in podocytes induces focal segmental glomerulosclerosis. J Am Soc Nephrol. 2011; 22: 1621-1630.

115. Blattner SM, Hodgin JB, Nishio M, Wylie SA, Saha J, Soofi AA, et al. Divergent functions of the Rho GTPases Rac1 and Cdc42 in podocyte injury. Kidney Int. 2013; 84: 920-930.

116. Gee HY, Saisawat P, Ashraf S, Hurd TW, Vega-Warner V, Fang H, et al. ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling. J Clin Invest. 2013; 123: 3243-3253.

117. Shin NY, Dise RS, Schneider-Mergener J, Ritchie MD, Kilkenny DM, Hanks SK. Subsets of the major tyrosine phosphorylation sites in Crk-associated substrate (CAS) are sufficient to promote cell migration. J Biol Chem. 2004; 279: 38331-38337.

118. Hanks SK, Ryzhova L, Shin NY, Brábek J. Focal adhesion kinase signaling activities and their implications in the control of cell survival and motility. Front Biosci. 2003; 8: d982-996.

119. Birge RB, Kalodimos C, Inagaki F, Tanaka S. Crk and CrkL adaptor proteins: networks for physiological and pathological signaling. Cell Commun Signal. 2009; 7: 13.

120. Ma H, Togawa A, Soda K, Zhang J, Lee S, Ma M, et al. Inhibition of podocyte FAK protects against proteinuria and foot process effacement. J Am Soc Nephrol. 2010; 21: 1145-1156.

121. Murea M, Park JK, Sharma S, Kato H, Gruenwald A, Niranjan T, et al. Expression of Notch pathway proteins correlates with albuminuria, glomerulosclerosis, and renal function. Kidney Int. 2010; 78: 514- 522.

122. Sharma M, Magenheimer LK, Home T, Tamano KN, Singhal PC, Hyink DP, et al. Inhibition of Notch pathway attenuates the progression of human immunodeficiency virus-associated nephropathy. Am J Physiol Renal Physiol. 2013; 304: F1127-36.

123. Giunta B, Ehrhart J, Obregon DF, Lam L, Le L, Jin J, et al. Antiretroviral medications disrupt microglial phagocytosis of β-amyloid and increase its production by neurons: implications for HIV-associated neurocognitive disorders. Mol Brain. 2011; 4: 23.

124. Barisoni L. Notch signaling: a common pathway of injury in podocytopathies? J Am Soc Nephrol. 2008; 19: 1045-1046.

125. Bonegio RG, Beck LH, Kahlon RK, Lu W, Salant DJ. The fate of Notchdeficient nephrogenic progenitor cells during metanephric kidney development. Kidney Int. 2011; 79: 1099-1112.

126. Cheng HT, Kopan R. The role of Notch signaling in specification of podocyte and proximal tubules within the developing mouse kidney. Kidney Int. 2005; 68: 1951-1952.

127. Cheng HT, Kim M, Valerius MT, Surendran K, Schuster-Gossler K, Gossler A, et al. Notch2, but not Notch1, is required for proximal fate acquisition in the mammalian nephron. Development. 2007; 134: 801-811.

128. Djudjaj S, Chatziantoniou C, Raffetseder U, Guerrot D, Dussaule JC, Boor P, et al. Notch-3 receptor activation drives inflammation and fibrosis following tubulointerstitial kidney injury. J Pathol. 2012; 228: 286-99.

129. Sharma M, Callen S, Zhang D, Singhal PC, Vanden Heuvel GB, Buch S. Activation of Notch signaling pathway in HIV-associated nephropathy. AIDS. 2010; 24: 2161-2170.

130. Kretzler M, Allred L. Notch inhibition reverses kidney failure. Nat Med. 2008; 14: 246-247.

131. Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell. 2006; 124: 471-484.

132. Huang J, Manning BD. The TSC1-TSC2 complex: a molecular switchboard controlling cell growth. Biochem J. 2008; 412: 179-190.

133. Kim DH, Sarbassov DD, Ali SM, King JE, Latek RR, ErdjumentBromage H, et al. mTOR interacts with raptor to form a nutrientsensitive complex that signals to the cell growth machinery. Cell. 2002; 110: 163-175.

134. Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR, ErdjumentBromage H, et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol. 2004; 14: 1296-302.

135. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005; 307: 1098-1101.

136. Toblli JE, Bevione P, Di Gennaro F, Madalena L, Cao G, Angerosa M. Understanding the mechanisms of proteinuria: therapeutic implications. Int J Nephrol. 2012; 2012: 546039.

137. Johnson SC, Rabinovitch PS, Kaeberlein M. mTOR is a key modulator of ageing and age-related disease. Nature. 2013; 493: 338-345.

138. Ito N, Nishibori Y, Ito Y, Takagi H, Akimoto Y, Kudo A, et al. mTORC1 activation triggers the unfolded protein response in podocytes and leads to nephrotic syndrome. Lab Invest. 2011; 91: 1584-1595.

139. Rangan GK, Coombes JD. Renoprotective effects of sirolimus in non- immune initiated focal segmental glomerulosclerosis. Nephrol Dial Transplant. 2007; 22: 2175-2182

140. Bonegio RG, Fuhro R, Wang Z, Valeri CR, Andry C, Salant DJ, et al. Rapamycin ameliorates proteinuria-associated tubulointerstitial inflammation and fibrosis in experimental membranous nephropathy. J Am Soc Nephrol. 2005; 16: 2063-72.

141. Naumovic R, Jovovic D, Basta-Jovanovic G, Miloradovic Z, MihailovicStanojevic N, Aleksic T, et al. Effects of rapamycin on active Heymann nephritis. Am J Nephrol. 2007; 27: 379-389.

142. Kurayama R, Ito N, Nishibori Y, Fukuhara D, Akimoto Y, Higashihara E, et al. Role of amino acid transporter LAT2 in the activation of mTORC1 pathway and the pathogenesis of crescentic glomerulonephritis. Lab Invest. 2011; 91: 992-1006.

143. Yang Y, Wang J, Qin L, Shou Z, Zhao J, Wang H, et al. Rapamycin prevents early steps of the development of diabetic nephropathy in rats. Am J Nephrol. 2007; 27: 495-502.

144. Gödel M, Hartleben B, Herbach N, Liu S, Zschiedrich S, Lu S, et al. Role of mTOR in podocyte function and diabetic nephropathy in humans and mice. J Clin Invest. 2011; 121: 2197-2209.

145. Huber TB, Walz G, Kuehn EW. mTOR and rapamycin in the kidney: signaling and therapeutic implications beyond immunosuppression. Kidney Int. 2011; 79: 502-511.

Arif E, Nihalani D (2013) Podocytes as a therapeutic target. Ann Clin Exp Hypertension 1(1): 1004.

Received : 16 Dec 2013
Accepted : 19 Dec 2013
Published : 19 Dec 2013
Annals of Otolaryngology and Rhinology
ISSN : 2379-948X
Launched : 2014
JSM Schizophrenia
Launched : 2016
Journal of Nausea
Launched : 2020
JSM Internal Medicine
Launched : 2016
JSM Hepatitis
Launched : 2016
JSM Oro Facial Surgeries
ISSN : 2578-3211
Launched : 2016
Journal of Human Nutrition and Food Science
ISSN : 2333-6706
Launched : 2013
JSM Regenerative Medicine and Bioengineering
ISSN : 2379-0490
Launched : 2013
JSM Spine
ISSN : 2578-3181
Launched : 2016
Archives of Palliative Care
ISSN : 2573-1165
Launched : 2016
JSM Nutritional Disorders
ISSN : 2578-3203
Launched : 2017
Annals of Neurodegenerative Disorders
ISSN : 2476-2032
Launched : 2016
Journal of Fever
ISSN : 2641-7782
Launched : 2017
JSM Bone Marrow Research
ISSN : 2578-3351
Launched : 2016
JSM Mathematics and Statistics
ISSN : 2578-3173
Launched : 2014
Journal of Autoimmunity and Research
ISSN : 2573-1173
Launched : 2014
JSM Arthritis
ISSN : 2475-9155
Launched : 2016
JSM Head and Neck Cancer-Cases and Reviews
ISSN : 2573-1610
Launched : 2016
JSM General Surgery Cases and Images
ISSN : 2573-1564
Launched : 2016
JSM Anatomy and Physiology
ISSN : 2573-1262
Launched : 2016
JSM Dental Surgery
ISSN : 2573-1548
Launched : 2016
Annals of Emergency Surgery
ISSN : 2573-1017
Launched : 2016
Annals of Mens Health and Wellness
ISSN : 2641-7707
Launched : 2017
Journal of Preventive Medicine and Health Care
ISSN : 2576-0084
Launched : 2018
Journal of Chronic Diseases and Management
ISSN : 2573-1300
Launched : 2016
Annals of Vaccines and Immunization
ISSN : 2378-9379
Launched : 2014
JSM Heart Surgery Cases and Images
ISSN : 2578-3157
Launched : 2016
Annals of Reproductive Medicine and Treatment
ISSN : 2573-1092
Launched : 2016
JSM Brain Science
ISSN : 2573-1289
Launched : 2016
JSM Biomarkers
ISSN : 2578-3815
Launched : 2014
JSM Biology
ISSN : 2475-9392
Launched : 2016
Archives of Stem Cell and Research
ISSN : 2578-3580
Launched : 2014
Annals of Clinical and Medical Microbiology
ISSN : 2578-3629
Launched : 2014
JSM Pediatric Surgery
ISSN : 2578-3149
Launched : 2017
Journal of Memory Disorder and Rehabilitation
ISSN : 2578-319X
Launched : 2016
JSM Tropical Medicine and Research
ISSN : 2578-3165
Launched : 2016
JSM Head and Face Medicine
ISSN : 2578-3793
Launched : 2016
JSM Cardiothoracic Surgery
ISSN : 2573-1297
Launched : 2016
JSM Bone and Joint Diseases
ISSN : 2578-3351
Launched : 2017
JSM Bioavailability and Bioequivalence
ISSN : 2641-7812
Launched : 2017
JSM Atherosclerosis
ISSN : 2573-1270
Launched : 2016
Journal of Genitourinary Disorders
ISSN : 2641-7790
Launched : 2017
Journal of Fractures and Sprains
ISSN : 2578-3831
Launched : 2016
Journal of Autism and Epilepsy
ISSN : 2641-7774
Launched : 2016
Annals of Marine Biology and Research
ISSN : 2573-105X
Launched : 2014
JSM Health Education & Primary Health Care
ISSN : 2578-3777
Launched : 2016
JSM Communication Disorders
ISSN : 2578-3807
Launched : 2016
Annals of Musculoskeletal Disorders
ISSN : 2578-3599
Launched : 2016
Annals of Virology and Research
ISSN : 2573-1122
Launched : 2014
JSM Renal Medicine
ISSN : 2573-1637
Launched : 2016
Journal of Muscle Health
ISSN : 2578-3823
Launched : 2016
JSM Genetics and Genomics
ISSN : 2334-1823
Launched : 2013
JSM Anxiety and Depression
ISSN : 2475-9139
Launched : 2016
Clinical Journal of Heart Diseases
ISSN : 2641-7766
Launched : 2016
Annals of Medicinal Chemistry and Research
ISSN : 2378-9336
Launched : 2014
JSM Pain and Management
ISSN : 2578-3378
Launched : 2016
JSM Women's Health
ISSN : 2578-3696
Launched : 2016
Clinical Research in HIV or AIDS
ISSN : 2374-0094
Launched : 2013
Journal of Endocrinology, Diabetes and Obesity
ISSN : 2333-6692
Launched : 2013
Journal of Substance Abuse and Alcoholism
ISSN : 2373-9363
Launched : 2013
JSM Neurosurgery and Spine
ISSN : 2373-9479
Launched : 2013
Journal of Liver and Clinical Research
ISSN : 2379-0830
Launched : 2014
Journal of Drug Design and Research
ISSN : 2379-089X
Launched : 2014
JSM Clinical Oncology and Research
ISSN : 2373-938X
Launched : 2013
JSM Bioinformatics, Genomics and Proteomics
ISSN : 2576-1102
Launched : 2014
JSM Chemistry
ISSN : 2334-1831
Launched : 2013
Journal of Trauma and Care
ISSN : 2573-1246
Launched : 2014
JSM Surgical Oncology and Research
ISSN : 2578-3688
Launched : 2016
Annals of Food Processing and Preservation
ISSN : 2573-1033
Launched : 2016
Journal of Radiology and Radiation Therapy
ISSN : 2333-7095
Launched : 2013
JSM Physical Medicine and Rehabilitation
ISSN : 2578-3572
Launched : 2016
Annals of Clinical Pathology
ISSN : 2373-9282
Launched : 2013
Annals of Cardiovascular Diseases
ISSN : 2641-7731
Launched : 2016
Journal of Behavior
ISSN : 2576-0076
Launched : 2016
Annals of Clinical and Experimental Metabolism
ISSN : 2572-2492
Launched : 2016
Clinical Research in Infectious Diseases
ISSN : 2379-0636
Launched : 2013
JSM Microbiology
ISSN : 2333-6455
Launched : 2013
Journal of Urology and Research
ISSN : 2379-951X
Launched : 2014
Journal of Family Medicine and Community Health
ISSN : 2379-0547
Launched : 2013
Annals of Pregnancy and Care
ISSN : 2578-336X
Launched : 2017
JSM Cell and Developmental Biology
ISSN : 2379-061X
Launched : 2013
Annals of Aquaculture and Research
ISSN : 2379-0881
Launched : 2014
Clinical Research in Pulmonology
ISSN : 2333-6625
Launched : 2013
Journal of Immunology and Clinical Research
ISSN : 2333-6714
Launched : 2013
Annals of Forensic Research and Analysis
ISSN : 2378-9476
Launched : 2014
JSM Biochemistry and Molecular Biology
ISSN : 2333-7109
Launched : 2013
Annals of Breast Cancer Research
ISSN : 2641-7685
Launched : 2016
Annals of Gerontology and Geriatric Research
ISSN : 2378-9409
Launched : 2014
Journal of Sleep Medicine and Disorders
ISSN : 2379-0822
Launched : 2014
JSM Burns and Trauma
ISSN : 2475-9406
Launched : 2016
Chemical Engineering and Process Techniques
ISSN : 2333-6633
Launched : 2013
Annals of Clinical Cytology and Pathology
ISSN : 2475-9430
Launched : 2014
JSM Allergy and Asthma
ISSN : 2573-1254
Launched : 2016
Journal of Neurological Disorders and Stroke
ISSN : 2334-2307
Launched : 2013
Annals of Sports Medicine and Research
ISSN : 2379-0571
Launched : 2014
JSM Sexual Medicine
ISSN : 2578-3718
Launched : 2016
Annals of Vascular Medicine and Research
ISSN : 2378-9344
Launched : 2014
JSM Biotechnology and Biomedical Engineering
ISSN : 2333-7117
Launched : 2013
Journal of Hematology and Transfusion
ISSN : 2333-6684
Launched : 2013
JSM Environmental Science and Ecology
ISSN : 2333-7141
Launched : 2013
Journal of Cardiology and Clinical Research
ISSN : 2333-6676
Launched : 2013
JSM Nanotechnology and Nanomedicine
ISSN : 2334-1815
Launched : 2013
Journal of Ear, Nose and Throat Disorders
ISSN : 2475-9473
Launched : 2016
JSM Ophthalmology
ISSN : 2333-6447
Launched : 2013
Journal of Pharmacology and Clinical Toxicology
ISSN : 2333-7079
Launched : 2013
Annals of Psychiatry and Mental Health
ISSN : 2374-0124
Launched : 2013
Medical Journal of Obstetrics and Gynecology
ISSN : 2333-6439
Launched : 2013
Annals of Pediatrics and Child Health
ISSN : 2373-9312
Launched : 2013
JSM Clinical Pharmaceutics
ISSN : 2379-9498
Launched : 2014
JSM Foot and Ankle
ISSN : 2475-9112
Launched : 2016
JSM Alzheimer's Disease and Related Dementia
ISSN : 2378-9565
Launched : 2014
Journal of Addiction Medicine and Therapy
ISSN : 2333-665X
Launched : 2013
Journal of Veterinary Medicine and Research
ISSN : 2378-931X
Launched : 2013
Annals of Public Health and Research
ISSN : 2378-9328
Launched : 2014
Annals of Orthopedics and Rheumatology
ISSN : 2373-9290
Launched : 2013
Journal of Clinical Nephrology and Research
ISSN : 2379-0652
Launched : 2014
Annals of Community Medicine and Practice
ISSN : 2475-9465
Launched : 2014
Annals of Biometrics and Biostatistics
ISSN : 2374-0116
Launched : 2013
JSM Clinical Case Reports
ISSN : 2373-9819
Launched : 2013
Journal of Cancer Biology and Research
ISSN : 2373-9436
Launched : 2013
Journal of Surgery and Transplantation Science
ISSN : 2379-0911
Launched : 2013
Journal of Dermatology and Clinical Research
ISSN : 2373-9371
Launched : 2013
JSM Gastroenterology and Hepatology
ISSN : 2373-9487
Launched : 2013
TEST Journal of Dentistry
ISSN : 1234-5678
Launched : 2014
Annals of Nursing and Practice
ISSN : 2379-9501
Launched : 2014
JSM Dentistry
ISSN : 2333-7133
Launched : 2013
Author Information X