[Synaptopodin: an actin-associated protein of telencephalic dendrites and of podocytes in the kidney glomerulus].
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Actins↗
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Biology of cultured podocytes.
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Basement Membrane↗
Long-term treatment of rats with FGF-2 results in focal segmental glomerulosclerosis.
Long-term treatment (8 and 13 weeks) of rats with FGF-2 led to albuminuria and to increase in serum creatinine indicating the development of chronic renal failure. Histologically, the classic picture of focal segmental glomerulosclerosis (FSGS) was found; males were more severely affected than females. Among the early changes podocyte lesions were most prominent. Surprisingly, mitotic figures in podocytes and a considerable fraction of bi(multi)nucleated podocyte profiles were found in treated animals (roughly 16% in males, 8% in females). Since an increase of cell number of podocytes was not evident, we conclude that FGF-2 stimulates podocytes to re-enter the cell cycle and to undergo mitosis (nuclear division). However, podocytes-probably due to their highly differentiated cell shape in the adult-are unable to complete cell division (cytokinesis) resulting in bi- or multinucleated cells; in others cell division may fail totally leading to podocyte degeneration. Most podocytes in FGF-2-treated rats exhibited degenerative changes including cell body attenuation, extensive pseudocyst formation, widespread foot process effacement, as well as detachments from the glomerular basement membrane (GBM). The development of FSGS in this model is very uniform. In the case of podocyte detachments from peripheral capillaries, parietal cells become attached to naked GBM-areas, establishing the nidus for development of a tuft adhesion to Bowman's capsule. Tuft adhesions grow by encroaching of parietal cells onto adjacent capillary loops, resulting eventually in a solid synechia with collapsed capillaries, that is, what represents segmental sclerosis. The distribution of adhesions on the inner surface of Bowman's capsule appeared to be random, including all locations between the vascular and urinary pole. The two main aspects of this study (inability of podocytes to replicate and development of FSGS based on progressing podocyte degeneration) may be part of a vicious cycle. FGF-2 stimulates podocytes to enter cell division thereby conveying them into a hazardous situation. If a podocyte fails and degenerates it cannot be replaced, aggravating the situation for the remaining cells and possibly increasing their predisposition to respond to mitogenic stimuli. Similar mechanisms may constitute the development of FSGS in other experimental as well as human glomerulopathies.
Animals↗
The parietal epithelial cell: a key player in the pathogenesis of focal segmental glomerulosclerosis in Thy-1.1 transgenic mice.
Focal segmental glomerulosclerosis (FSGS) is a hallmark of progressive renal disease. Podocyte injury and loss have been proposed as the critical events that lead to FSGS. In the present study, the authors have examined the development of FSGS in Thy-1.1 transgenic (tg) mice, with emphasis on the podocyte and parietal epithelial cell (PEC). Thy-1.1 tg mice express the Thy-1.1 antigen on podocytes. Injection of anti-Thy-1.1 mAb induces an acute albuminuria and development of FSGS lesions that resemble human collapsing FSGS. The authors studied FSGS lesions at days 1, 3, 6, 7, 10, 14, and 21, in relation to changes in the expression of specific markers for normal podocytes (WT-1, synaptopodin, ASD33, and the Thy-1.1 antigen), for mouse PEC (CD10), for activated podocytes (desmin), for macrophages (CD68), and for proliferation (Ki-67). The composition of the extracellular matrix (ECM) that forms tuft adhesions or scars was studied using mAb against collagen IV alpha2 and alpha4 chains and antibodies directed against different heparan sulfate species. The first change observed was severe PEC injury at day 1, which increased in time, and resulted in denuded segments of Bowman's capsule at days 6 and 7. Podocytes showed foot process effacement and microvillous transformation. There was no evidence of podocyte loss or denudation of the GBM. Podocytes became hypertrophic at day 3, with decreased expression of ASD33 and synaptopodin and normal expression of WT-1 and Thy-1.1. Podocyte bridges were formed by attachment of hypertrophic podocytes to PEC and podocyte apposition against denuded segments of Bowman's capsule. At day 6, there was a marked proliferation of epithelial cells in Bowman's space. These proliferating cells were negative for desmin and all podocyte markers, but stained for CD10, and thus appeared to be PEC. The staining properties of the early adhesions were identical to that of Bowman's capsule, suggesting that the ECM in the adhesions was produced by PEC. In conclusion, the authors propose the following sequence of events leading to FSGS lesions in the Thy1.1 tg mice: (1) PEC damage and denudation of Bowman's capsule segments; (2) podocyte hypertrophy and bridging; and (3) PEC proliferation with ECM production.
Animals↗
Cellular response to injury in membranous nephropathy.
The pathogenesis of membranous nephropathy (MN) involves in situ formation of subepithelial immune deposits that produce glomerular injury by damaging and/or activating podocytes through complement-dependent processes. C5b-9 formation and insertion into podocyte cell membranes causes glomerular injury in MN. C5b-9 in sublytic quantities stimulates podocytes to produce proteases, oxidants, prostanoids, extracellular matrix components, and cytokines including TGF-beta. C5b-9 also causes alterations of the cytoskeleton that lead to abnormal distribution of slit diaphragm protein and detachment of viable podocytes that are shed into Bowman's space. These events result in disruption of the functional integrity of the glomerular basement membrane and the protein filtration barrier of podocytes with subsequent development of massive proteinuria. Complement components in proteinuric urine also induce tubular epithelial cell injury and mediate progressive interstitial disease in MN. Measurements of urinary C5b-9 or podocyte excretion in the urine may be useful in the diagnosis of MN and as measures of disease activity and response to therapy. Recent studies of cell-cycle proteins and DNA damage in podocytes have clarified why podocytes fail to proliferate in response to C5b-9-mediated injury and podocyte loss in MN, resulting in the development of glomerular sclerosis and renal failure. Improved understanding of the role of complement in the pathogenesis of MN and of the cellular response to C5b-9 attack creates several new opportunities for therapeutic intervention that may benefit patients with MN in the future.
Complement Membrane Attack Complex↗
Posttransplantation relapse of FSGS is characterized by glomerular epithelial cell transdifferentiation.
This study examined six cases of idiopathic nephrotic syndrome with primary lesions of focal segmental glomerulosclerosis (FSGS) that relapsed after renal transplantation. The glomerular lesions comprised the cellular, the collapsing, and the scar variants of FSGS and showed shedding of large round cells into Bowman's space and within the tubular lumens. Immunohistochemistry and confocal laser microscopy carried out on kidneys with FSGS relapse disclosed several phenomena. (1) Some podocytes that expressed podocalyxin, synaptopodin, and glomerular epithelial protein-1 were detached from the tuft and were free in the urinary space. (2) In the cellular variant, most podocytes had lost podocyte-specific epitopes (podocalyxin, synaptopodin, glomerular epithelial protein-1, Wilm's tumor protein-1, complement receptor-1, and vimentin). In the scar variant, these podocyte markers were absent from cobblestone-like epithelial cells and from pseudotubules. (3) Podocytes had acquired expression of various cytokeratins (CK; identified by the AE1/AE3, C2562, CK22, and AEL-KS2 monoclonal antibodies) that were not found in the podocytes of control glomeruli. Parietal epithelial cells expressed AE1/AE3 CK that were faintly, if ever, found on the parietal epithelial cells of normal glomeruli. (4) Numerous cells located at the periphery of the tuft or free in Bowman's space and within tubular lumens expressed macrophagic epitopes (identified by PGM1 [CD68], HAM56, and 25F9 monoclonal antibodies). These macrophage-like cells expressed the activation epitopes HLA-DR and CD16. (5) A number of these cells coexpressed podocalyxin + AE1/AE3 CK, podocalyxin + CD68, and CD68 + AE1/AE3. These findings suggest that in primary FSGS relapsing on transplanted kidneys, some "dysregulated" podocytes, occasionally some parietal epithelial cells, and possibly some tubular epithelial cells undergo a process of transdifferentiation. This process of transdifferentiation was especially striking in podocytes that acquired macrophagic and CK epitopes that are absent from normal adult and fetal podocytes.
Antigens, CD↗
Tuft-to-capsule adhesions and their precursors: differences between the vascular and tubular poles of the human glomerulus.
Human glomerular capillary tufts were removed by microdissection and scanning electron microscopy was used to examine the surface of the capillary tuft and the interior of its Bowman's capsule in order to identify connections between the tuft and capsule. Glomeruli were examined in histologically normal renal cortex from 12 kidneys removed for tumour and 12 renal allografts removed for end-stage rejection. In normal kidney, the glomerular tuft was connected to Bowman's capsule by single podocytes and their processes. At the vascular pole, these were predominantly associated with parietal podocytes which lined Bowman's capsule. At the tubular pole, occasional podocytic processes derived from the capillary tuft bridged Bowman's space and connected to Bowman's capsule where there were no parietal podocytes. These podocytic connections were also found in all rejected transplants, but in addition adhesions were identified which consisted of thicker connections between the tuft and capsule. At the vascular pole, tuft-to-capsule adhesions were found in all 12 kidneys; these were always associated with parietal podocytes. Tubular pole adhesions were identified in ten of the 12 transplants. They were associated with abnormal squamous cells, but not with parietal podocytes. When the capillary tuft herniated into the proximal tubule, the tuft sometimes formed an adhesion with the origin of the proximal tubule. These observations suggest that podocyte connections between the glomerular tuft and Bowman's capsule may be precursors of glomerular adhesions at the vascular pole. Since tuft-to-capsule adhesions at the vascular pole differ morphologically from those at the tubular pole, this may reflect different pathogenetic mechanisms at the opposite poles of the glomerulus.
Chronic Disease↗
Morphological alterations of the glomerular (visceral) epithelium in response to pathological and experimental situations.
The glomerular (visceral) layer of Bowman's capsule is comprised of a unique population of cells which have been termed "podocytes." Arising from these cells are large major processes and numerous smaller foot processes which completely surround underlying glomerular capillary loops. Podocyte foot processes interdigitate with each other and are separated by spaces (filtration slits) which are designed to facilitate flow of a large amount of filtrate across the glomerular wall. Podocytes exhibit dramatic morphological changes in response to the nephrotic syndrome and some forms of acute renal failure and may play an important role in the pathophysiology of these conditions. In vitro and in vivo studies have shown that a reduction in the sialic acid component of a thick anionic surface coat plays a major role in the morphological changes that these cells exhibit in the nephrotic syndrome. Also, it has been shown that filamentous actin concentrated mainly within podocyte foot processes are the contractile elements responsible for altering the shapes of these processes. There is evidence to suggest that by altering the shapes of their foot processes, podocytes in the normal kidney are able to alter the number of fully patent filtration slits and thereby actively regulate the rate of solute efflux across the glomerular wall. In vitro and in vivo studies have indicated that cytoplasmic microtubules are probably not involved in alterations of the podocyte foot processes but do appear important in maintaining the morphological integrity of podocyte cell bodies and their major processes. In the present paper, the morphological changes which glomerular podocytes exhibit in response to the nephrotic syndrome, various forms of acute renal failure, and during in vitro incubation are discussed along with studies of the possible roles of cytoplasmic microtubules, microtubules, and the glomerular anionic surface coat in these changes.
Acute Kidney Injury↗
Human immunodeficiency virus-1 tat induces hyperproliferation and dysregulation of renal glomerular epithelial cells.
Human immunodeficiency virus-associated nephropathy (HIVAN) is etiologically related to the viral infection, but the mechanisms of virus-induced renal injury remain undetermined. Peculiar histopathological features of HIVAN are the enhanced proliferation and the loss of differentiation markers of glomerular epithelial cells (podocytes). We found that podocytes were not permissive to HIV-1 replication. In this study we investigated the effects of the HIV-1 regulatory protein Tat on primary cultures and on a continuous line of podocytes. Our results demonstrated that Tat induced hyperproliferation of these cells in a dose-dependent manner. This activity was primarily mediated by the basic domain of the viral protein. Proteoglycans were required for this phenomenon because Tat-induced increase of podocyte growth was significantly impaired by inhibition of proteoglycan synthesis with beta-D-xyloside. In podocyte cultures Tat promoted both the transcription and the release of basic fibroblast growth factor, which contributed to the enhanced cell proliferation. Moreover, Tat deregulated the podocyte phenotype causing down-regulation of maturity markers such as WT-1 and synaptopodin, alteration of cytoarchitecture, and impairment of permselectivity. Together, these results demonstrate that the interaction of extracellular Tat with podocytes can induce alterations that mimic the pathological changes of podocytes detected in HIVAN.
Cell Division↗
A novel role for the adaptor molecule CD2-associated protein in transforming growth factor-beta-induced apoptosis.
CD2-associated protein (CD2AP) is an adaptor molecule involved in T cell receptor signaling and podocyte homeostasis. CD2AP-deficient mice develop nephrotic syndrome and renal failure caused by glomerulosclerosis. Here we report that increased transforming growth factor-beta1 (TGF-beta1) expression and apoptosis were present in podocytes at the onset of albuminuria and were followed by depletion of podocytes associated with progressive focal-segmental glomerulosclerosis in CD2AP-/- mice. Conditionally immortalized podocytes derived from CD2AP-/- mice were more susceptible to TGF-beta-induced apoptosis compared with CD2AP+/+ podocytes. Reconstitution of CD2AP rescued CD2AP-/- podocytes from TGF-beta-induced apoptosis. CD2AP was required for early activation of anti-apoptotic phosphatidylinositol 3-kinase (PI3K)/AKT and extracellular signal-regulated kinase 1/2 by TGF-beta. In contrast, activation of pro-apoptotic p38 MAPK by TGF-beta was accelerated and enhanced in the absence of CD2AP. CD2AP was not required for PI3K/AKT activation by insulin and epidermal growth factor, indicating that CD2AP is a selective mediator of anti-apoptotic TGF-beta signaling. In summary, we identified CD2AP as a novel mediator for selective activation of survival pathways and repression of apoptosis signaling by TGF-beta in podocytes. Together, our in vitro and in vivo findings suggest that TGF-beta-induced podocyte apoptosis is an early pathomechanism in mice developing focal-segmental glomerulosclerosis associated with functional impairment of CD2AP.
Adaptor Proteins, Signal Transducing↗
Synaptopodin regulates the actin-bundling activity of alpha-actinin in an isoform-specific manner.
Synaptopodin is the founding member of a novel class of proline-rich actin-associated proteins highly expressed in telencephalic dendrites and renal podocytes. Synaptopodin-deficient (synpo(-/-)) mice lack the dendritic spine apparatus and display impaired activity-dependent long-term synaptic plasticity. In contrast, the ultrastructure of podocytes in synpo(-/-) mice is normal. Here we show that synpo(-/-) mice display impaired recovery from protamine sulfate-induced podocyte foot process (FP) effacement and LPS-induced nephrotic syndrome. Similarly, synpo(-/-) podocytes show impaired actin filament reformation in vitro. We further demonstrate that synaptopodin exists in 3 isoforms, neuronal Synpo-short (685 AA), renal Synpo-long (903 AA), and Synpo-T (181 AA). The C terminus of Synpo-long is identical to that of Synpo-T. All 3 isoforms specifically interact with alpha-actinin and elongate alpha-actinin-induced actin filaments. synpo(-/-) mice lack Synpo-short and Synpo-long expression but show an upregulation of Synpo-T protein expression in podocytes, though not in the brain. Gene silencing of Synpo-T abrogates stress-fiber formation in synpo(-/-) podocytes, demonstrating that Synpo-T serves as a backup for Synpo-long in synpo(-/-) podocytes. In concert, synaptopodin regulates the actin-bundling activity of alpha-actinin in highly dynamic cell compartments, such as podocyte FPs and the dendritic spine apparatus.
Actinin↗
Angiotensin II type 1 receptor blockade inhibits the development and progression of HIV-associated nephropathy in a mouse model.
HIV-associated nephropathy (HIVAN) is characterized by a collapsed glomerular capillary tuft with hyperplasia and hypertrophy of podocytes. Recently generated were conditional transgenic mice (podocin/Vpr) that express one of the HIV-1 accessory genes, vpr, selectively in podocytes using podocin promoter and Tet-on system. These transgenic mice developed renal injury similar to HIVAN when treated with doxycycline for 8 to 12 wk. This study demonstrated that nephron reduction by heminephrectomy markedly enhanced phenotypic changes of podocytes and led to severe FSGS within 4 wk. Nephrotic-range proteinuria was observed already at 2 wk, together with dedifferentiation and dysregulation of podocytes, indicated by decreased expression of nephrin, synaptopodin, and Wilms' tumor 1 protein and increased expression of Ki-67. The acceleration of phenotypic changes of podocytes, proteinuria, and subsequent glomerulosclerosis by heminephrectomy was almost completely inhibited by angiotensin II type 1 receptor (AT1R) blocker olmesartan. In contrast, the renoprotective effect of the calcium channel antagonist azelnidipine was minimal, although it lowered systemic BP to the same level as olmesartan, demonstrating that the inhibitory effect of AT1R blocker was independent of systemic BP. Olmesartan also reduced proteinuria and prevented glomerulosclerosis even by the delayed treatment, which was initiated after the podocyte injury appeared. These data suggest that nephron reduction exaggerates podocyte injury and subsequent glomerulosclerosis, possibly through glomerular hypertension, in the mouse model of HIVAN. AT1R blockade could be beneficial in the treatment of HIVAN by ameliorating podocyte injury by avoiding the vicious cycle of nephron reduction and glomerular hypertension.
AIDS-Associated Nephropathy↗
Glomerulocystic kidney disease in a Belgian Malinois dog: an ultrastructural, immunohistochemical, and lectin-binding study.
Renal cysts in the cortex of a juvenile Belgian Malinois dog with acute renal failure were studied by means of light, scanning and transmission electron microscopy, immunohistochemistry for intermediate filaments, and binding for wheat germ agglutinin (WGA), peanut agglutinin (PNA), and Maclura pomifera agglutinin (MPA) lectins to determine the morphological and histochemical features of the epithelial cells of these cysts. The cysts were renal corpuscles with expanded urinary space. Glomerular tufts were small with poorly developed capillary loops and increased mesangial matrix. Continuity with the proximal tubule was evident in some cystic glomeruli. Two cell types lined Bowman's capsule. One was squamous with a central cilium and microvilli. The other had morphological and histochemical features of immature podocytes (parietal podocytes). These cells were round and protruded into the urinary space; they had thick cytoplasmic projections that resembled foot processes of podocytes, microvilli, and filtration slits. The parietal podocytes expressed vimentin and cytokeratins and had affinity for WGA as do normal immature podocytes. These features suggest that the parietal podocytes are derived by metaplasia of the parietal cells. The basement membrane of Bowman's capsule was irregularly thickened and showed multifocal glycosylation changes with lectin histochemistry (WGA, PNA, MPA) in areas adjacent to the parietal podocytes. Histologic and ultrastructural findings in this dog are consistent with glomerulocystic kidney disease. This is the second report of canine glomerulocystic kidney disease. Features are similar to those of the human counterpart, but it is unclear whether genetic defects cause the disease in the dog. The presence of parietal podocytes in all cysts suggests that abnormal differentiation may play an important role in the pathogenesis of this type of polycystic kidney disease.
Animals↗
Characterization of free surface microprojections on the kidney glomerular epithelium.
Scanning and transmission electron microscopy were used to evaluate free surface microprojections on the kidney glomerular epithelium in response to various experimental situations. Normally glomerular epithelial podocytes exhibit a rather sparse population of finger-like or bleb-like projections. Some investigations, however, have suggested that microvillous projections may increase in number during the differentiation of podocytes and in the aging kidney. With the onset of puromycin aminonucleoside induced nephrotic syndrome, podocyte microprojections become very knob-like and irregular in their shapes. In response to the in vitro environment, the number of podocyte microprojections increases dramatically. Neuraminidase removal of the sialic acid component of the glomerular glycocalyx and exposure to either cytochalasin B (25 microgram/ml) or cytochalasin D (2 microgram/ml), prevent the in vitro formation of podocyte microprojections. In vitro incubation in compounds which depolymerize cytoplasmic microtubules (e.g. vinblastine sulfate 10(-5); colchicine 10(-5) M), however, result in the formation of unusually long glomerular epithelial microprojections. Investigations utilizing the cationic ligand polycationized ferritin (PCF) have shown that podocyte microprojections are the most anionic sites on the free surfaces of these cells. During prolonged incubation of PCF treated glomeruli, the tips of podocyte microprojections are the last sites to shed the anionically bound PCF. It is suggested that the highly anionic sialic acid components of the glomerular free surface glycocalyx may play principal roles in the formation, maintenance and shapes of glomerular podocyte microprojections.
Animals↗
Math6 expression during kidney development and altered expression in a mouse model of glomerulosclerosis.
Math6 is a tissue-restricted member of the Atonal family of basic helix-loop-helix (bHLH) transcription factors and has been implicated in specification and differentiation of cell lineages in the brain. We identify here Math6 as a podocyte-expressed bHLH protein that was down-regulated in human immunodeficiency virus-associated nephropathy (HIVAN); a collapsing glomerulopathy characterized by podocyte dedifferentiation. Early in metanephric development, Math6 was expressed in metanephric mesenchyme but not ureteric bud-derived cells, with overall Math6 expression most abundant in the nephrogenic zone, including developing glomeruli. In adult kidney, Math6 expression was restricted to podocytes. In adult podocyte cell lines and kidneys from the transgenic mouse model of HIVAN, Math6 podocyte expression was reduced concurrent with previously reported reductions in Nephrin and Synaptopodin expression, suggesting a correlation between the loss of Math6 expression and typical podocyte terminal differentiation markers. These studies suggest that Math6 may participate in kidney development and may be a permissive factor for podocyte differentiation.
Amino Acid Sequence↗
Organization of the pronephric filtration apparatus in zebrafish requires Nephrin, Podocin and the FERM domain protein Mosaic eyes.
Podocytes are specialized cells of the kidney that form the blood filtration barrier in the kidney glomerulus. The barrier function of podocytes depends upon the development of specialized cell-cell adhesion complexes called slit-diaphragms that form between podocyte foot processes surrounding glomerular blood vessels. Failure of the slit-diaphragm to form results in leakage of high molecular weight proteins into the blood filtrate and urine, a condition called proteinuria. In this work, we test whether the zebrafish pronephros can be used as an assay system for the development of glomerular function with the goal of identifying novel components of the slit-diaphragm. We first characterized the function of the zebrafish homolog of Nephrin, the disease gene associated with the congenital nephritic syndrome of the Finnish type, and Podocin, the gene mutated in autosomal recessive steroid-resistant nephrotic syndrome. Zebrafish nephrin and podocin were specifically expressed in pronephric podocytes and required for the development of pronephric podocyte cell structure. Ultrastructurally, disruption of nephrin or podocin expression resulted in a loss of slit-diaphragms at 72 and 96 h post-fertilization and failure to form normal podocyte foot processes. We also find that expression of the band 4.1/FERM domain gene mosaic eyes in podocytes is required for proper formation of slit-diaphragm cell-cell junctions. A functional assay of glomerular filtration barrier revealed that absence of normal nephrin, podocin or mosaic eyes expression results in loss of glomerular filtration discrimination and aberrant passage of high molecular weight substances into the glomerular filtrate.
Amino Acid Sequence↗
Glomerular localization of erythropoietin receptor mRNA and protein in neonatal and mature mouse kidney.
BACKGROUND/AIMS: Erythropoietin (EPO) possesses well-established hematopoietic properties as the primary stimulator of red blood cell formation by binding to its receptor (EPO-R). Recent evidence suggests pathophysiological roles of EPO in several non-hematopoietic tissues including kidney. Our aim was to further clarify the glomerular localization of EPO-R in normal kidney, as well as changes in its expression during glomerulogenesis. METHODS: We analyzed EPO-R mRNA and protein expression in neonatal and adult mouse kidney by in situ hybridization and immunohistochemistry. To confirm the precise localization and developmental changes of EPO-R expression in podocytes in mature and developing glomeruli, we examined co-expression with the podocyte markers WT-1 and synaptopodin. RESULTS: In addition to tubular expression as reported recently, EPO-R expression was observed in podocytes as well as endocapillary cells in the glomeruli from adult mice. In newborn kidney, EPO-R mRNA and protein expression was first observed in developing podocytes in S-shaped bodies with expression subsequently increasing in glomeruli at the capillary-loop and maturing stages. Immunoelectron microscopy also demonstrated cytoplasmic expression of EPO-R that was prominent at the basal sides of podocytes in glomeruli at the late capillary-loop and maturing stage. CONCLUSION: EPO-R is expressed in developing and mature podocytes in mouse kidney, suggesting a possible role for EPO in podocyte biology.
Animals↗
The mouse Kreisler (Krml1/MafB) segmentation gene is required for differentiation of glomerular visceral epithelial cells.
Molecular components of the glomerular filtration mechanism play critical roles in renal diseases. Many of these components are produced during the final stages of differentiation of glomerular visceral epithelial cells, also known as podocytes. While basic domain leucine zipper (bZip) transcription factors of the Maf subfamily have been implicated in cellular differentiation processes, Kreisler (Krml1/MafB), the gene affected in the mouse kreisler (kr) mutation, is known for its role in hindbrain patterning. Here we show that mice homozygous for the kr(enu) mutation develop renal disease and that Kreisler is essential for cellular differentiation of podocytes. Consistent with abnormal podocyte differentiation, kr(enu) homozygotes show proteinuria, and fusion and effacement of podocyte foot processes, which are also observed in the nephrotic syndrome. Kreisler acts during the final stages of glomerular development-the transition between the capillary loop and mature stages-and downstream of the Pod1 basic domain helix-loop-helix transcription factor. The levels of Podocin, the gene mutated in autosomal recessive steroid-resistant nephrotic syndrome (NPHS2), and Nephrin, the gene mutated in congenital nephrotic syndrome of the Finnish type (NPHS1), are slightly reduced in kr(enu)/kr(enu) podocytes. However, these observations alone are unlikely to account for the aberrant podocyte foot process formation. Thus, Kreisler must regulate other unknown genes required for podocyte function and with possible roles in kidney disease.
Animals↗