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PubMed2006

Renal bone morphogenetic protein-7 protects against diabetic nephropathy.

Longstanding diabetes causes renal injury with early dropout of podocytes, albuminuria, glomerular and tubulointerstitial fibrosis, and progressive renal failure. The renal pathology seems to be driven, in part, by TGF-beta and is associated with a loss of renal bone morphogenic protein-7 (BMP-7) expression. Here, the hypothesis that maintenance of renal (especially podocyte) BMP-7 by transgenic expression reduces diabetic renal injury was tested. Diabetic mice that expressed the phosphoenolpyruvate carboxykinase promoter-driven BMP-7 transgene and nondiabetic, transgenic mice as well as diabetic and nondiabetic wild-type controls were studied for up to 1 yr. Transgenic expression of BMP-7 in glomerular podocytes and proximal tubules prevents podocyte dropout and reductions in nephrin levels in diabetic mice. Maintenance of BMP-7 also reduces glomerular fibrosis and interstitial collagen accumulation as well as collagen I and fibronectin expression. Diabetic wild-type mice develop progressive albuminuria, which is substantially reduced in transgenic mice. These effects of the BMP-7 transgene occur without changing renal TGF-beta levels. It is concluded that maintenance of renal BMP-7 during the evolution of diabetic nephropathy reduces diabetic renal injury, especially podocyte dropout. The findings also establish a role for endogenous glomerular BMP-7 as an autocrine regulator of podocyte integrity in vivo.

Animals↗
PubMed2006

TGF-beta1 regulates the PINCH-1-integrin-linked kinase-alpha-parvin complex in glomerular cells.

Glomerular damage is a major cause of renal failure. Recent studies suggest that a ternary protein complex that consists of PINCH-1, integrin-linked kinase, and alpha-parvin, cytoplasmic components of cell-extracellular matrix adhesions, plays pivotal roles in regulation of glomerular cell behavior. It is reported here that TGF-beta1, a key factor in the progression of glomerular failure, regulates the PINCH-1-integrin-linked kinase-alpha-parvin (PIP) complex formation in glomerular podocytes and mesangial cells. Treatment of podocytes with TGF-beta1 inhibited the PIP complex formation. Forced disruption of the PIP complex in podocytes activated p38 mitogen-activated protein kinase and promoted apoptosis. Importantly, inhibition of p38 mitogen-activated protein kinase, either with a chemical p38 inhibitor (SB202190) or with a dominant negative form of p38alpha, alleviates podocyte apoptosis that is induced by the disruption of the PIP complex. In contrast to an inhibitory role in podocytes, TGF-beta1 promotes the PIP complex formation in mesangial cells. Thus, TGF-beta1 regulates the PIP complex in a cell type-dependent manner. Because the PIP complex promotes glomerular mesangial matrix deposition and protects podocytes from apoptosis, the TGF-beta1-induced up- and downregulation of the PIP complex likely contribute to the pleiotropic effects of TGF-beta1 on different glomerular cell types and hence the progression of glomerular failure.

Actinin↗
PubMed1989

Differential expression of galactose and N-acetylgalactosamine residues during fetal development and postnatal maturation of rat glomeruli as revealed with lectin conjugates.

A battery of fluorochrome- or peroxidase-coupled lectins, reacting with alpha- or beta-galactose (Gal), terminal N-acetylgalactosamine (GalNAc), or Gal-(beta 1-3)-GalNAc residues, was used to study the emergence and distribution of cellular glycoconjugates in developing and adult rat glomeruli. Neuraminidase pretreatment of the specimens was applied to monitor the maturation of the glomerular sialoglycoprotein coat. In the adult glomeruli, the lectin conjugates applied reacted sparsely or not at all, but most of them showed an increased reactivity with podocytes and/or the glomerular basement membrane after neuraminidase treatment. In the embryonic glomeruli, lectins reacting with beta-Gal residues prominently bound to the basement membranes, as revealed in double-staining with laminin antibodies. This reactivity decreased first during late postnatal development. Some terminal Gal-(beta 1-3)-GalNAc residues were noted in the earliest podocytes, but obviously soon became covered by sialylation. Furthermore, the developing podocytes prominently displayed alpha-Gal residues, as marked by Maclura pomifera (MPA) and Jacalin reactivities but not by the GSA-I conjugates. During postnatal maturation these reactivities also decreased. The GalNAc-specific Helix pomatia (HPA) and Helix aspersa (HAA) agglutinins bound to basement membranes of evolving podocytes but later revealed in the podocytes only a Golgi-like cytoplasmic reactivity. These two lectins showed a marked difference in their binding to tubular basement membranes. In lectin blotting experiments of electrophoretically separated polypeptides transferred onto nitrocellulose, the peanut agglutinin (PNA) and MPA conjugates revealed upon neuraminidase treatment a broad Mr 140,000 polypeptide, compatible with podocalyxin, both in isolated developing and adult glomeruli. The MPA conjugate revealed a similar polypeptide in developing glomeruli, even without neuraminidase treatment. Similar experiments with the HPA and HAA conjugates revealed different polypeptides in both adult and developing glomeruli. Obviously, in the rat kidney the maturation of the podocyte sialoglycoprotein coat and the glomerular basement membranes are multiphasic processes that continue even during late postnatal development.

Acetylgalactosamine↗
PubMed2004

The dysregulated glomerular cell growth in Denys-Drash syndrome.

While diffuse mesangial sclerosis is traditionally described as being the glomerulopathy of Denys-Drash syndrome (DDS), the podocyte proliferative lesions may be overlooked in these DDS cases. In the present study, an evolving process is extrapolated from a selected case of DDS that demonstrated glomerulopathy with conspicuous podocyte proliferation. The observation that podocytes express proliferation markers (Ki67, proliferating-cell nuclear antigen and topoisomerase IIalpha) in non-proliferative, mature-looking glomeruli suggests an initial pathogenic act to activate or to keep podocytes from quiescence. The subsequent proliferation of podocytes is in keeping with downregulation of WT1 and cyclin kinase inhibitors of p16 and p21. The emergence of cytokeratin-positive cells in glomeruli that show typical mesangial sclerosis implies elimination of podocytes and replacement with tubular and/or parietal epithelial cells. The final scene of evolving glomerulopathy displays apoptosis and expression of Fas-L and Bax in sclerotic mesangial lesions, which eventually end up with global sclerosis. This novel concept of DDS glomerulopathy implies complex molecular mechanisms involved in glomerular injury.

Antigens, Neoplasm↗
PubMed2000

Expression of agrin, dystroglycan, and utrophin in normal renal tissue and in experimental glomerulopathies.

The dystrophin-glycoprotein complex, which comprises alpha- and beta-dystroglycan, sarcoglycans, and utrophin/dystrophin, links the cytoskeleton to agrin and laminin in the basal lamina in muscle and epithelial cells. Recently, agrin was identified as a major heparan sulfate proteoglycan in the glomerular basement membrane. In the present study, we found mRNA expression for agrin, dystroglycan, and utrophin in kidney cortex, isolated glomeruli, and cultured podocytes and mesangial cells. In immunofluorescence, agrin was found in the glomerular basement membrane. The antibodies against alpha- and beta-dystroglycan and utrophin revealed a granular podocyte-like staining pattern along the glomerular capillary wall. With immunoelectron microscopy, agrin was found in the glomerular basement membrane, dystroglycan was diffusely found over the entire cell surface of the podocytes, and utrophin was localized in the cytoplasm of the podocyte foot processes. In adriamycin nephropathy, a decrease in the glomerular capillary wall staining for dystroglycan was observed probably secondary to the extensive fusion of foot processes. Immunoelectron microscopy showed a different distribution pattern as compared to the normal kidney, with segmentally enhanced expression of dystroglycan at the basal side of the extensively fused podocyte foot processes. In passive Heymann nephritis we observed no changes in the staining intensity and distribution of the dystrophin-glycoprotein complex by immunofluorescence and immunoelectron microscopy. From these data, we conclude that agrin, dystroglycan, and utrophin are present in the glomerular capillary wall and their ultrastructural localization supports the concept that these molecules are involved in linking the podocyte cytoskeleton to the glomerular basement membrane.

Agrin↗
PubMed2003

Pathobiochemistry of nephrotic syndrome.

Nephrotic syndrome is a clinical and laboratory syndrome caused by the increased permeability of the glomerular capillary wall for macromolecules. Nephrotic syndrome is a potentially life-threatening state and persistent nephrotic syndrome has a poor prognosis with a high risk of progression to end-stage renal failure and a high risk of cardiovascular complications due to severe hyperlipidemia. Pathogenesis of increased glomerular permeability in different glomerular diseases has not been fully elucidated. Recently, identification of the mutated genes for some podocyte proteins (nephrin, podocin, alpha-actinin-4) in rare familial forms of nephrotic syndrome shed has new light on the molecular mechanisms of glomerular permselectivity. Gradually it becomes apparent that sporadic mutations of podocyte proteins (e.g., podocin) may be present even in some patients with acquired nephrotic syndrome. Expression of other podocyte proteins may change during the course of experimental nephrotic syndrome, possibly as a response to podocyte damage resulting either in apoptosis or stimulation of proliferation and some form of repair, including glomerular sclerosis. Better understanding of these mechanisms could clearly also have therapeutic implications. Glomerular permeability factors are believed to play a role in some noninflammatory glomerular diseases, mainly minimal change disease and focal segmental glomerulosclerosis, but their molecular identification remains elusive, possibly due to the nonhomogeneous nature of the underlying diseases. As an example, focal segmental glomerulosclerosis possibly can be caused by the sporadic mutation of some genes for podocyte proteins, increased production of glomerular permeability factor (possibly by T lymphocytes), or the loss of inhibitors of glomerular permeability factors in nephrotic urine. Clearly the factors causing increased glomerular permeability and factors perpetuating glomerular sclerosis are not necessarily the same. Proteinuria does not seem to be only the consequence of glomerular damage, but it may possibly cause tubular damage and initiate interstitial fibrosis and thus contribute to the progression of chronic renal failure in proteinuric renal diseases. Recent insights into the mechanisms of tubular protein reabsorption may give new tools for preventing the progression of chronic renal disease. Cubilin inhibitors could potentially ameliorate tubular and interstitial damage in patients with heavy proteinuria refractory to treatment. Nephrotic hyperlipidemia is accompanied with increased risk of cardiovascular complications and should be treated in all patients with persistent nephrotic syndrome. The putative positive effect of hypolipidemic drugs (namely statins) on the cardiovascular risk and potentially also on the rate of progression of chronic renal failure remains to be demonstrated in prospective controlled studies. Recent progress in understanding podocyte biology in rare inherited glomerular diseases gives the chance to understand in the near future the molecular pathogenesis of increased glomerular permeability in the much more common acquired forms of nephrotic syndrome.

Animals↗
PubMed1981

Investigations of cytoplasmic contractile and cytoskeletal elements in the kidney glomerulus.

Electron microscopy and in vitro techniques were used to evaluate the morphologic responses of glomerular podocytes and glomerular endothelial cells to compounds that affect either cytoplasmic contractile elements or cytoplasmic microtubules. In response to in vitro incubation in the presence of cytochalasin D or B (compounds that inhibit contraction of actin-like microfilaments), podocyte foot processes change in shape from short processes with broad bases to taller processes with narrow bases. Coincident with these shape changes, there is an increase in the number of fully patent filtration slit spaces between adjacent foot processes. In view of these observations, it is proposed that glomerular podocytes have the potential for monitoring the filtration slit area available for solute efflux across the glomerular wall by modifying the shapes of their foot processes (that is, expanding and contracting the bases of these structures). As in vitro incubation continues for 1 to 2 days, the cytochalasins inhibit the shape changes of glomerular podocytes that normally occur during 2 days of in vitro incubation--the loss of foot processes, filtration slits, endothelial pores, and thickening of the endothelium. The cytochalasins also inhibit the loss of foot processes and filtration slits that otherwise occur in response to enzymatic removal of glomerular-free surface sialic acid. The in vitro depolymerization of glomerular microtubules by any of a variety of drugs (for example, vinblastine sulfate, colchicine) results in the rounding up of podocyte cell bodies, the thinning of podocyte major processes, and a partial collapsing of the glomerular endothelial walls. These latter observations suggest that microtubules play an important cytoskeletal role in maintaining the structural integrity of these cells.

Animals↗
PubMed1996

Stability and leakiness: opposing challenges to the glomerulus.

The complex architecture of the glomerular tuft is stabilized by several mechanisms. The basic system consists of the GBM and the mesangium maintaining the branching pattern of the capillary network. Superimposed are the podocytes, which appear to take effect by two mechanisms. First, podocytes contribute to the stabilization of the capillary folding pattern by supporting the angles between neighboring capillaries. Second, podocyte foot processes fixed to the outer aspect of the GBM probably function as contractile patches counteracting the elastic distension of the GBM. Simultaneously, the pattern of foot process interdigitation underlies the elaboration of a filtration slit and is thus pivotal for the high hydraulic permeability and the specificity of the glomerular filter. The loss of this pattern-commonly termed "foot process effacement" or "foot process fusion"-is frequently found in pathological situations and results in a decrease in permeability and impairment in specificity. On the other hand, foot process effacement is associated with prominent hypertrophy of the contractile apparatus of podocytes, suggesting an increased ability to generate forces counteracting capillary expansion. Thus, foot process effacement appears as an adaptive change in podocyte phenotype giving priority to the support function of podocytes for the prize of reducing the specific permeability.

Animals↗
PubMed2000

Molecular cloning, expression, and distribution of glomerular epithelial protein 1 in developing mouse kidney.

BACKGROUND: Glomerular epithelial protein 1 (GLEPP1) is a receptor-like membrane protein tyrosine phosphatase (RPTP) with a large ectodomain consisting of multiple fibronectin type III repeats, a single transmembrane segment, and a single cytoplasmic phosphatase active site sequence. In adult human and rabbit kidneys, GLEPP1 is found exclusively on apical membranes of podocytes and especially on surfaces of foot processes. Although neither ligand nor function for this protein is known, other RPTPs with similar topologies have been implicated in mediating adherence behavior of cells. METHODS: To evaluate potential roles of GLEPP1 further, we cloned the full-length mouse GLEPP1 cDNA and examined its expression patterns in developing kidney by Northern blot analysis, in situ hybridization, and immunofluorescence microscopy. RESULTS: Nucleotide sequencing showed that mouse GLEPP1 was approximately 80% identical to rabbit and human GLEPP1 and approximately 91% identical at the amino acid level. The membrane-spanning and phosphatase domains of mouse GLEPP1 shared> 99% homology with PTPphi, a murine macrophage cytoplasmic phosphatase. Northern analysis identified a single GLEPP1 transcript of approximately 5.5 kb in fetal kidney that became approximately threefold more abundant in adults. In situ hybridization of newborn mouse kidney revealed GLEPP1 mRNA in visceral epithelial cells (developing podocytes) of comma- and S-shaped nephric figures, and expression increased in capillary loop and maturing stage glomeruli. Beginning on embryonic day 14, GLEPP1 protein was first observed on cuboidal podocytes of capillary loop stage glomeruli, but nascent podocytes of earlier comma- and S-shaped nephric figures were negative. At later stages of glomerular maturation, where foot process elongation and interdigitation occurs, GLEPP1 immunolabeling intensified on podocytes and then persisted at high levels in fully developed glomeruli. CONCLUSION: Our findings are consistent with a role for GLEPP1 in mediating and maintaining podocyte differentiation specifically.

Amino Acid Sequence↗
PubMed2003

E pluribus unum: The riddle of focal segmental glomerulosclerosis.

A recent consensus conference proposed a new classification for focal segmental glomerulosclerosis (FSGS). Five patterns have been defined: FSGS not otherwise specified, perihilar variant, cellular variant, tip variant, and collapsing variant. In light of the multiplicity of classification schemes in use, the promise of a rational and uniform scheme for FSGS pathology is most welcome. This approach has worked extremely well for the classification of lupus nephritis. It does not necessarily mean, however, that this new classification scheme will help to select treatment protocols according to histopathologic subsets of FSGS. In fact, one renal biopsy examination may show multiple variants and this classification, despite many merits, still lumps categories that should be split and splits categories that should be lumped together. It has become clear that despite its histologic diversity FSGS begins as a podocyte disease that progresses from a cellular to a scar lesion. Recent years have brought about astonishing insight into the complex molecular array of proteins forming the slit diaphragm between podocyte foot processes, a narrow space essential for restricting glomerular permeability to albumin. Concentrating on the podocyte rather than on the glomerular tuft is helpful for abolishing the classic distinction between primary versus secondary forms of FSGS, a distinction that crumbles away with each new evidence of genetic, ischemic, or viral etiologies of FSGS, despite similar lesions. In fact, recent studies focusing on the podocyte changes that occur in various subsets of FSGS have unraveled the striking phenomena of podocyte dedifferentiation and transdifferentiation along with differential expression of cyclin-dependent kinase inhibitors. Interestingly, the latter showed that expression of cyclin-dependent kinase inhibitors p21 and proliferation marker Ki-67 are the same in cellular FSGS, collapsing glomerulopathy, and human immunodeficiency virus-associated FSGS. Taken together these findings lead to a reassuring unitary interpretation of the pluralistic appearance of FSGS by histopathology. Clearly, further studies of the podocyte will lead to improved understanding of FSGS and to improved classification schemes that are grounded in molecular understanding of glomerular injury and that will guide the clinician in the choice of treatment and prognosis.

Animals↗
PubMed2004

A podocentric view of nephrology.

PURPOSE OF REVIEW: The glomerular visceral epithelial cell plays a central role in ultrafiltration of the blood and in a wide variety of inherited and acquired diseases of the kidney. The discovery of nephrin and other slit diaphragm proteins has led to an explosion of knowledge in the biology of this cell type. The most significant recent discoveries are reviewed in this paper. RECENT FINDINGS: Together with the glomerular endothelial cells and intervening glomerular basement membrane, the podocyte constitutes a major portion of the glomerular filtration barrier that separates blood from the urinary space. A number of proteins have been identified that are localized to the slit diaphragms that separate podocyte foot processes. Although it has been suggested that the slit diaphragm represents the ultimate filtration barrier, additional roles for this structure as a signaling centre and in endocytosis have been identified. Mutations in genes that reside in the slit pore or interact with the actin cytoskeleton have been linked to a variety of inherited diseases of the podocyte. Additional mutations in these genes have been linked to sporadic forms of nephrotic syndrome and proposed as modifiers of renal risk. The generation of podocyte-specific transgenic models and genomic tools for the murine podocyte provide important resources for the glomerular biologist. SUMMARY: Over the past year, studies using human genetics, conditional gene targeting and cell biological approaches have led to a rapid increase in our understanding of podocyte and glomerular biology, which should lead to the development of novel therapies for individuals with glomerular disease.

Animals↗
PubMed1999

Origin of hyperplastic epithelial cells in idiopathic collapsing glomerulopathy.

AIMS: Glomerular epithelial cell hypertrophy and hyperplasia are listed as the primary criteria for the diagnosis of collapsing glomerulopathy (CG), a distinct variant of focal segmental glomerulosclerosis. However, the extent of podocyte phenotypic alterations that occur in CG, and the origin of the hyperplastic epithelial cells remain to be established. METHODS AND RESULTS: Renal biopsy materials from seven out of three patients with CG were studied by serial section analysis for immunohistochemistry and electron microscopy. Markers for podocytes (PHM5 and synaptopodin), parietal epithelial cells (PECs: cytokeratin) and macrophages (CD68) were used for the immunohistochemistry. Multiple ultrathin sections from a total of 15 glomeruli, including some from patients with CG, were examined by electron microscopy. Glomerular adhesions occurred in 71% of the serially sectioned glomeruli taken from patients with CG. Hyperplastic epithelial cells were immunonegative for podocyte markers and CD68, but invariably immunopositive for cytokeratin. Electron microscopy revealed that detachment of the podocytes from involved glomerular capillary walls was extensive. Many of the detached podocytes appeared to be necrotic and apoptotic. In contrast, junctional complexes of desmosomes and zonula adherens connected hyperplastic epithelial cells to each other. Cilia were also often observed. CONCLUSIONS: The results of our ultrastructural and immunohistochemical study suggest that the hyperplastic epithelial cells observed in cases of CG are derived from PECs. Our results raise the possibility that PECs play a general role in covering glomerular tufts from which the podocytes have disappeared.

Adult↗
PubMed2000

Early mechanisms of renal injury in hypercholesterolemic or hypertriglyceridemic rats.

Hyperlipidemia in conjunction with uninephrectomy leads to renal injury in rats. It is unknown whether this is due to mesangial cell or podocyte injury and whether the injuries induced by hypercholesterolemia and hypertriglyceridemia share a similar pathogenesis. Therefore, renal effects of hypercholesterolemia were studied in male rats with dietary hypercholesterolemia compared with rats on a regular diet. Renal effects of hypertriglyceridemia were studied in female Nagase analbuminemic rats (NAR). Hypertriglyceridemia was reduced in NAR by ovariectomy. Both models were studied after uninephrectomy or sham operation. Dietary hypercholesterolemia had little effect on plasma triglycerides, whereas ovariectomy in the NAR had no effect on plasma cholesterol. However, an increase in intermediate density lipoprotein cholesterol was common to both models. Dietary hypercholesterolemia and uninephrectomy separately induced a similar increase in proteinuria after 13 wk, which was additive when these interventions were combined. At this stage, only a minimal increase was present in glomerular alpha-smooth muscle actin staining, a marker of mesangial cell activation, or in mesangial matrix expansion. Moreover, platelet-derived growth factor-B chain, a marker of mesangial cell proliferation, was not increased. However, podocyte injury was prominent as evidenced by podocytic de novo expression of desmin and ultrastructural changes. Glomerular macrophage counts were increased by hypercholesterolemia but not by uninephrectomy, and were not related to the level of proteinuria. Hypertriglyceridemia and uninephrectomy in female NAR induced an increase in proteinuria after 24 wk, which was also associated with an increase in podocyte desmin expression without any mesangial activation and proliferation or matrix accumulation. Hypertriglyceridemia, proteinuria, and the increase in desmin staining were largely prevented by ovariectomy. Interstitial myofibroblast activation and tubulointerstitial injury accompanied proteinuria in both models. These findings indicate that both hypercholesterolemia and hypertriglyceridemia aggravate renal injury primarily via podocyte rather than via mesangial cell damage. Such podocyte injury is accompanied by tubulointerstitial cell activation and injury.

Animals↗
PubMed1983

A scanning electron microscope study of isolated glomeruli in glomerulonephritis.

Glomeruli from 48 cases of glomerulonephritis (Gn) were isolated and studied by means of the scanning electron microscope (SEM). Overall glomerular loss due to processing was 2.4%. SEM of these isolated glomeruli showed good preservation of glomerular structure. Changes of the podocyte cell body and its foot processes were noted and correlated with light microscopic morphology. Individual podocyte necrosis, variable foot process fusion and cell body swelling were seen in IgA nephropathy. Podocyte degeneration with separation from the glomerular basement membrane was evident in idiopathic minimal change Gn while idiopathic membranous Gn was characterized by globular swelling of the podocyte cell bodies. In focal sclerosing Gn, large spherical bodies arising from swollen podocyte cell bodies were frequently encountered. Innumerable microvilli and small spherical bodies characterized membranoproliferative Gn. Variable podocyte cell body swelling, microvilli and small spherical bodies were seen in cases of lupus nephritis. Taken alone, none of the SEM changes were diagnostic. However, when the type of the change, the severity and the combination of the changes were considered as a whole, they were indicative of what light microscopy might reveal and helpful in differentiating between idiopathic minimal change Gn and focal sclerosing Gn.

Basement Membrane↗
PubMed1999

[Morphometric analysis of normal glomerular epithelial cells in rat and human].

It has been postulated that morphological changes of podocytes might be related to glomerular sclerotic lesions in experimental models and patients with glomerular diseases. To estimate the absolute number of podocytes in mammalian normal glomerulus, we analyzed normal glomeruli in four rats and six humans. In PAS stained light microscopic sections, at least 25 midsections of open glomeruli were photographed. Stereologic estimation was performed to obtain the following values: absolute values of glomerular volume (V), glomerular surface area (S), podocyte and intraglomerular cell number per glomerulus (P and IGC), glomerular surface area covered by one podocyte (S/P) and glomerular volume occupied by one intraglomerular cell (V/IGC). The glomerular volume, glomerular surface area and podocyte and intraglomerular cell numbers per glomerulus of human were significantly increased compared with those of the rat (V: 2.70 +/- 0.86 > 0.89 +/- 0.19, S: 4.84 +/- 1.26 > 1.88 +/- 0.26, P: 407.7 +/- 88.2 > 153.8 +/- 84.0, p < 0.01 vs rat). On the other hand, there were no significant differences in glomerular surface area covered by one podocyte and glomerular volume occupied by one intraglomerular cell between the humans and rats (S/P: 1.25 +/- 0.20, 1.29 +/- 0.05, V/IGC: 2,471 +/- 487, 2,227 +/- 201, p < 0.01 vs rat). These data were almost the same as previously reported values. It appears that these values can be considered as standards for rats and humans in morphometric analysis of the glomerulus.

Adolescent↗
PubMed1980

In vitro studies of kidney glomerular epithelial cells.

An in vitro model system for studying the glomerular epithelium exposed on the surfaces of kidney slices is described. In the first 12 hours of incubation at 37 degrees C, glomerular podocytes exhibit an increase in number of free surface microprojections and number of cytoplasmic lipid inclusions. During the next several days these cells undergo a series of morphological alterations which resemble a dedifferentiation of the glomerular epithelium. By one week of incubation, the glomerular epithelium has been transformed into a compact group of rounded cells. These cells remain rounded but viable throughout several weeks of subsequent incubation. The glomerular endothelium becomes thickened but also remains viable throughout several weeks of incubation. Surface epithelial cells in both cortical and medullary regions become modified into a thin layer of viable cells. At lower incubation temperatures (e.g. 15 to 33 degrees C), the dedifferentiation of glomerular podocytes and formation of a viable surface layer of cells are significantly inhibited. Both undifferentiated and puromycin aminonucleoside nephrotic glomerular podocytes survive and adapt to the in vitro environment. The in vitro response of glomerular epithelial cells to various compounds added to the incubation media are briefly described. Compounds which induce a loss of cytoplasmic microtubules (e.g. vinblastine, colchicine), cause a loss of podocyte cell body and major process morphological integrity. Neuraminidase removal of the glomerular sialic acid surface coat inhibits the formation of free surface microvilli and results in an early loss of podocyte foot processes. The nephrotoxic agent puromycin aminonucleoside has no effect on the viability or morphology of glomerular cells except at very high concentrations (300 micrograms/ml). The distribution and effects of polycationized ferritin on living glomeruli are briefly described. Finally, in vitro treatment with cytochalasin B appears to inhibit cation-induced loss of podocyte foot processes.

Animals↗
PubMed2005

The kd/kd mouse is a model of collapsing glomerulopathy.

Collapsing glomerulopathy (CG) is associated with disorders that markedly perturb the phenotype of podocytes. The kd/kd mouse has been studied for immune and genetic causes of microcystic tubulointerstitial nephritis with little attention to its glomerular lesion. Because histologic examination revealed classic morphologic features of CG, the question arises whether podocytes in kd/kd mice exhibit additional phenotypic criteria for CG. Utilizing Tg26 mice as a positive control, immunohistochemical profiling of the podocyte phenotype was conducted simultaneously on both models. Similar to Tg26 kidneys, podocytes in kd/kd kidneys showed de novo cyclin D1, Ki-67, and desmin expression with loss of synaptopodin and WT-1 expression. Electron micrographs showed collapsed capillaries, extensive foot process effacement, and dysmorphic mitochondria in podocytes. These results indicate that the kd/kd mouse is a model of CG and raise the possibility that human equivalents of the kd susceptibility gene may exist in patients with CG.

Animals↗
PubMed2006

Enhanced aldosterone signaling in the early nephropathy of rats with metabolic syndrome: possible contribution of fat-derived factors.

Metabolic syndrome is an important risk factor for proteinuria and chronic kidney disease independent of diabetes and hypertension; however, the underlying mechanisms have not been elucidated. Aldosterone is implicated in target organ injury of obesity-related disorders. This study investigated the role of aldosterone in the early nephropathy of 17-wk-old SHR/NDmcr-cp, a rat model of metabolic syndrome. Proteinuria was prominent in SHR/NDmcr-cp compared with nonobese SHR, which was accompanied by podocyte injury as evidenced by foot process effacement, induction of desmin and attenuation of nephrin. Serum aldosterone level, renal and glomerular expressions of aldosterone effector kinase Sgk1, and oxidative stress markers all were elevated in SHR/NDmcr-cp. Mineralocorticoid receptors were expressed in glomerular podocytes. Eplerenone, a selective aldosterone blocker, effectively improved podocyte damage, proteinuria, Sgk1, and oxidant stress. An antioxidant tempol also alleviated podocyte impairment and proteinuria, along with inhibition of Sgk1. As for the mechanisms of aldosterone excess, visceral adipocytes that were isolated from SHR/NDmcr-cp secreted substances that stimulate aldosterone production in adrenocortical cells. The aldosterone-releasing activity of adipocytes was not inhibited by candesartan. Adipocytes from nonobese SHR did not show such activity. In conclusion, SHR/NDmcr-cp exhibit enhanced aldosterone signaling, podocyte injury, and proteinuria, which are ameliorated by eplerenone or tempol. The data also suggest that adipocyte-derived factors other than angiotensin II might contribute to the aldosterone excess of this model.

Adipocytes↗