Novel concepts in understanding and management of glomerular proteinuria
Jochen Reiser,
Gero von Gersdorff,
Matias Simons,
Karin Schwarz,
Christian Faul,
Laura Giardino,
Torsten Heider,
Martin Loos and
Peter Mundel
Department of Medicine, and Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA
Keywords: angiotensin converting enzyme; angiotensin receptor blocker; glomerular permselectivity; lipid rafts; podocytes; proteinuria
Form follows function and time is precious: these principles are conflated in the glomerular podocyte. They define its function but also the necessity to limit the exposure of podocytes to injurious agents. A number of glomerular disorders that may lead to chronic kidney disease are characterized by simplification and retraction of podocyte foot processes (FP) (effacement). These structural podocyte defects are highly reversible for a certain time and every effort should be undertaken to prevent disease progression and the need for renal replacement therapy, which harbors enormous financial and human costs. Podocytes elaborate a network of processesmajor processes and FP, which surround glomerular capillaries. Together with the glomerular basement membrane (GBM) and the glomerular endothelial cells, podocytes provide the structural basis for glomerular filtration [1]. Although it is generally acknowledged that the GBM can restrict the passage of large plasma proteins, there is increasing evidence that the ultimate barrier for proteins larger than albumin is the slit diaphragm (SD). The past 4 years have been extremely fruitful in providing an extensive amount of information on the molecular composition of the SD, and opened up new avenues to understand podocyte function [2,3]. ACE inhibitors and angiotensin receptor blockers have proven effective in ameliorating glomerular proteinuria and slowing of disease progression in proteinuric renal diseases and in diabetic nephropathy in particular [48]. In addition, there are novel intriguing experimental data that link the salutary effects of these drugs to changes in the composition of the SD. This comment is focused on the recent progress in understanding the molecular mechanisms that underlie SD dysfunction and the development of proteinuria.
The slit diaphragm: a dynamic site of glomerular permselectivity
In the mature kidney the SD is the only site of cellcell contact between FP of adjacent podocytes. It represents a tiny membrane bridging the 3040 nm wide filtration slit. In 1974, Rodewald and Karnovsky [9] showed by transmission electron microscopy that the slit diaphragm is made up of rod-like units connected in the center to a linear bar forming a zipper-like appearance, but the nature of the components of the SD and its anchorage in the FP were still unknown. Twenty-five years later, the discovery of the transmembrane protein, nephrin, as a major component of the slit diaphragm complex [1012] provided a seminal progress in podocyte biology. Mutation analysis of the nephrin gene, NPHS1, by positional cloning elucidated the underlying genetic defect in Finnish type congenital nephrotic syndrome as causative for fusion of podocyte FP in this disease [13]. Similarly, injection of anti-nephrin antibody in animals induced substructural alterations of the SD with reduction of permselectivity and consecutive proteinuria [14]. The inactivation of the nephrin gene in mice by homozygous recombination resulted in reduction of visible SD, severe proteinuria and partial effacement of FP [15]. To date, the exact function of nephrin within the SD is not clear. Nephrin is a large (1241 amino acids, 185 kDa) transmembrane molecule with immunoglobulin-like domains. Its predicted structure and biochemical properties, as well as electron microscopy studies suggested that nephrin may form dimers through homophilic interactions across the filtration slit [16]. However, thus far, several laboratories have failed to show such an interaction, and the nephrin homologue in Drosophila, hibris, was found to form heterophilic interactions with a protein called dumbfounded, but did not form homophilic interactions with other hibris molecules [17,18]. Nephrin may also contribute functional properties to the SD, perhaps by participating in a protein complex in which interference with any of the components may lead to functional destabilization of the SD and consequent FP effacement and proteinuria. The list of proteins that comprise the SD is expanding rapidly. A homologue of nephrin, NEPH-1, was recently discovered using retrovirus-mediated mutagenesis [19]. The homozygous knockout mice of NEPH-1 show effacement of FP [19]. Whether NEPH-1 interacts with nephrin is not known at present.
At the intracellular insertion site of the SD, the adapter protein CD2AP has been localized [2022]. This protein was originally discovered as a protein interacting with the CD2 receptor in T-lymphocytes [23]. CD2AP is critical for orchestrating the so-called immunological synapse between B- and T-cells [23,24], but has gained an unexpected and important role in podocyte cell biology, as CD2AP knockout mice die several weeks after birth with effacement of FP and nephrotic syndrome [20]. CD2AP has been shown to interact with nephrin via a novel C-terminal domain [22] and is also capable of binding the actin cytoskeleton. The role of other molecules that are associated with the SD awaits clarification. ZO-1 has long been known to localize to the intracellular site of insertion of the SD. It interacts with the actin cytoskeleton and may also participate in signaling events through tyrosine phosphorylation [25]. It is worth noting that the redistribution of ZO-1 was associated with the development of proteinuria in spontaneously proteinuric MunichWistarFroemter (MWF) rats, although the podocyte FP were normal and the slit diaphragms preserved in these animals [26]. P-cadherin [27] and FAT [28], which are widely expressed cadherin superfamily proteins, define the SD as a modified adherens junction and may provide structural support to this specialized cellcell contact.
Involvement of lipid rafts in functional organization of the SD
Lipid raft microdomains are very important elements in the functional organization of the slit diaphragm [29,30]. Lipid rafts are specialized membrane domains enriched in cholesterol, glycosphingolipids and GPI-anchored proteins [31]. By compartmentalizing cell membranes, they recruit and cluster membrane proteins in a selective and dynamic fashion. Hereby, they provide molecular frameworks for numerous cell biological processes, such as exo- and endocytosis, cell adhesion and signal transduction events [32]. In a recent study from our laboratory, nephrin was found to be associated with lipid rafts [33]. Furthermore, nephrin could be co-immunoprecipitated by an antibody recognizing a podocyte-specific 9-O-acetylated ganglioside [33]. The in vivo injection of this antibody led to morphologic changes of the filtration slits resembling effacement of FP. In this model of FP effacement, nephrin dislocated to the apical pole of the narrowed filtration slits and underwent tyrosine phosphorylation [33]. Previous studies have described a role for tyrosine phosphorylation in the assembly and disassembly of the slit diaphragm [25]. It is unclear as yet which kinases are involved in regulating these events, but the genetic inactivation of the src family kinase fyn caused proteinuria in mice [34]. Interestingly, as a double-acylated molecule, fyn has a high affinity for lipid rafts [35,36]. Hence, it is intriguing to speculate that fyn is involved in regulating the dynamics of the SD complex.
Recently, podocin gained importance in podocyte biology. Its gene, NPHS2, was identified as a gene whose mutations cause autosomal recessive, steroid-resistant nephrotic syndrome [37]. Podocin is a new member of the stomatin family of hairpin-like integral membrane proteins with intracellular N- and C-termini. Stomatin is present as high-order oligomers in erythrocyte lipid rafts, where it has a scaffolding function [38]. Podocin was localized at the slit diaphragm [39,40], and accumulated there in an oligomeric form in lipid rafts. Moreover, podocin associated with CD2AP and nephrin via its C-terminus. Further studies revealed direct interaction of podocin and CD2AP [40]. Hence, podocin may act as a scaffolding protein, serving in the structural organization of the slit diaphragm and the regulation of its filtration function. In vitro co-expression studies showed that podocin facilitated nephrin signaling via AP-1 in HEK cells [41]. The relevance of this finding for podocyte biology remains to be established.
The response of podocytes to injury
Podocytes are injured in many forms of human and experimental glomerular disease, including minimal change disease, focal segmental glomerulosclerosis, membranous glomerulopathy, diabetes mellitus and lupus nephritis [2,3]. The early events are characterized either by alterations in the molecular composition of the slit diaphragm without visible changes in morphology or, more obviously, by a reorganization of FP structure with fusion of filtration slits and apical displacement of the slit diaphragm. Effacement of FP is accompanied by a reorganization of the actin cytoskeleton into a dense network [42], which is preceded by an induction of podocyte
-actinin expression [43]. The
-actinin-4 molecule is an actin filament cross-linker with an important function in podocytes. Its mutation, which has been demonstrated in an autosomal dominant form of focal segmental glomerular sclerosis (FSGS), highlights the exquisite role of the actin cytoskeleton in short- and long-term regulation of podocyte structure [44,45]. Based on recent insight into the molecular pathology of podocyte injury, at least five major causes have been identified that lead to the uniform reaction of FP effacement and proteinuria: (i) interference with the SD complex and its lipid rafts; (ii) direct interference with the actin cytoskeleton [43,44]; (iii) interference with the GBM or the podocyteGBM interaction [4653]; (iv) interference with the negative surface charge of podocytes [5457]; or (v) with the activity of GLEPP1, a membrane bound tyrosine phosphatase [58]. There is evidence in FSGS and in idiopathic nephrotic syndrome in rats that podocyte damage may be caused by circulating albuminuric factors [59,60].
Treatment of proteinuria and progression of renal disease by molecular modulation of podocyte function
It is important to recognize that early structural changes in podocyte morphology, such as substructural alterations in slit diaphragm composition or effacement of FP have to be reversed within a certain period of time to prevent development of severe and progressive glomerular damage [61]. There is strong clinical evidence that blockade of the reninangiotensinaldosterone (RAA) system by ACE inhibitors or angiotensin receptor blockers (ARB) decreases proteinuria [58]. There is also mounting evidence that decreasing proteinuria is associated with improved renal outcome regardless of the underlying disease process [62].
The effects of RAA blockade on podocytes have been shown in a variety of experimental settings. In experimental diabetic nephropathy, podocyte FP broadening was ameliorated by RAA blockade [63] and was associated with normalization of nephrin expression [64]. ACE inhibition stabilized the SD-associated protein ZO-1 in its original position and prevented the development of proteinuria in spontaneously proteinuric MWF rats [26]. Renal injury in passive Heyman nephritis was greatly diminished and the accompanying downregulation of nephrin gene expression was largely prevented by ACE [65]. Together, these data indicate that the salutary effects of RAA blockade of proteinuria, and ultimately disease progression, may be mediated at least in part by interference with SD composition and podocyte function. In this context, it is important to note that podocytes in the intact glomerulus respond to angiotensin II (AII) with an increase of intracellular [Ca2+] via an AT1 receptor [66]. Further studies are required to test the hypothesis that AII-mediated changes in intracellular calcium orchestrate the composition and function of the SD.
Outlook
Podocyte biology has progressed into a new era of understanding the molecular features of glomerular homeostasis and pathology. We have made dramatic progress in understanding the importance of the SD for the development of proteinuria. This will hopefully translate into more refined treatment and prevention of proteinuria and progressive renal disease.
Acknowledgments
We would like to thank Michael Dubenko for helpful discussion. G.v.G. is supported by a fellowship from the Lupus Foundation, K.S. by a fellowship from the National Kidney Foundation of New York/New Jersey, and L.G. by a Fellowship from the Associazione Nuova Nefrologia Ospedale San Carlo Borromeo, Milan, Italy. M.L. was supported by a student fellowship from the DAAD, Bonn, Germany. Work from our laboratory is supported by a grant from the National Institutes of Health (DK57683-01) to P.M.
Notes
The first two authors contributed equally to this work. 
Correspondence and offprint requests to: Peter Mundel, MD, Division of Nephrology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA. Email: mundel{at}aecom.yu.edu 
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