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PubMed1995

Podocytic degeneration and regeneration in puromycin aminonucleoside nephropathy in the rat.

In various types of chronic glomerulonephritis, proliferation of mesangial and endothelial cells is often seen together with extracellular matrix accumulation. In contrast, the proliferation of visceral glomerular epithelial cells (podocytes) has not been detected in any disease in which these cells are the principal target of injury. To examine whether proliferation of podocytes occurs, puromycin aminonucleoside nephropathy was induced in Wistar rats by intraperitoneal injection of puromycin aminonucleoside (15 mg/100 g of bodyweight). In this nephropathy model of nephrotic syndrome with minimal change, the main lesions consisted of vacuolation and flattened foot processes of podocytes, which are the primary target of puromycin aminonucleoside. Urine protein excretion and proliferating cell nuclear antigen (PCNA) positive cells were examined. The PCNA+ podocytic count reached its maximum on day 3, indicating that the most marked podocytic proliferation occurs just after the injection of PAN. Twenty-four hour urinary excretion in this nephropathy model supported the hypothesis that mitosis of podocytes occurs in association with recovery on day 13.

Animals↗
PubMed1995

Limitations of podocyte adaptation for glomerular injury in puromycin aminonucleoside nephrosis.

Glomerular synechiae that occurred in nephrotic rats with a single intraperitoneal injection of puromycin aminonucleoside were analyzed by immunohistochemistry, radiolabeled thymidine ([3H]-thymidine) autoradiography, as well as light, electron and immunoelectron microscopy. To discriminate podocytes from parietal epithelial cells (PEC) and monocytes, monoclonal antibodies (mAb) against podocalyxin and ED1 were used. The cell kinetics of glomerular epithelial cells were autoradiographically assessed with isotope labeling procedures before and during nephrosis (co-labeled), and a mAb against proliferating cell nuclear antigen (PCNA). All the cell types except the podocyte of normal kidneys were labelled with [3H]-thymidine at different rates. Detachment of degenerated podocytes from the outside of the glomerular basement membrane (GBM) is the first step of synechia, and detached sites are confronted by PEC that were hypertrophied and frequently radiolabeled. Evidence that podocytes in glomeruli of nephrotic rats can proliferate was shown by the presence of mitoses, [3H]-thymidine uptake in the co-labeled experiment, and by PCNA staining, but re-epithelialization over bare segments of the GBM with proliferated podocytes is doubtful. It was concluded that glomerular synechia resulted from the limits of podocyte adaptation to glomerular injuries.

Animals↗
PubMed2004

Estimation of podocyte number: a comparison of methods.

BACKGROUND: The podocyte is the focus of much research into the mechanisms of renal disease progression, and the number of podocytes per glomerulus has thus become a parameter of much interest. When counting podocytes, the actual particle counted is the cell nucleus. The majority of published studies estimating podocyte number have used the method of Weibel and Gomez (1962). This makes assumptions about the shape and size of the cell nuclei and therefore has an inherent bias. In our studies we have used a more recent stereologic method--the disector/fractionator--that makes no assumptions about the shape or size of the cell nuclei and is therefore free of bias. METHODS: We set out to compare the two methods, in both type 1 diabetic patients and normal controls, to determine whether eliminating bias and thus improving accuracy had any effect on the overall results. The Weibel-Gomez method estimates cell number from a single section through the glomerulus, whereas the disector/fractionator requires the glomerulus to be serially sectioned. RESULTS: There was no significant difference between mean values obtained by the two methods, providing that the Weibel-Gomez estimate was performed on electron micrographs. However, the overall variance was high for all groups of patients, independent of the method employed. CONCLUSION: Although the disector/fractionator is the theoretic gold standard method for podocyte number estimation, comparable estimates can be obtained by the Weibel-Gomez method provided they are made from electron micrographs. Thus the technical resources available may determine the choice of method employed. Investigators should be aware of the high degree of variability in the estimate, particularly when trying to detect small changes in podocyte number.

Biopsy↗
PubMed2004

C-type natriuretic peptide as a podocyte hormone and modulation of its cGMP production by glucose and mechanical stress.

BACKGROUND: High glucose and mechanical strain resulting from capillary hypertension are relevant risk factors affecting glomerular cells in diabetes. Altered activity of the natriuretic peptide (NP) system acting via vasorelaxing cyclic guanosine 5' monophosphate (cGMP) has been proposed to be one of the reasons for diabetes-dependent impairment of kidney function. Podocytes possess the NP receptors (NPRs) coupled to particular guanylyl cyclase. We investigated whether mechanical stress and high ambient glucose influence cGMP generation in podocytes stimulated with NPs. Additionally, the C-type natriuretic peptide (CNP) system has been characterized in these cells. METHODS: Conditionally immortalized mouse podocytes were stimulated with NP for 15 minutes and cGMP was determined by enzymatic immunoassay. The mRNA expression for CNP and CNP-specific NPR-B was confirmed by reverse transcriptase-polymerase chain reaction (RT-PCR). In addition, cGMP synthesis was measured in cells exposed to mechanical stress and to 30 mmol/L glucose for 3 days. RESULTS: Production of cGMP upon stimulation of the NPR-B receptor with CNP and inhibition by an antagonist HS-142-1 was dose-dependent. RT-PCR showed that podocytes express mRNA not only for NPR-B but also for CNP. Mechanical stress reduced the cGMP response by 50%, both to atrial natriuretic peptide (ANP) and to CNP. Conversely, upon high glucose, the CNP-induced production of cGMP was elevated twofold in stretched and in control cells. Furthermore, as compared to ANP, stimulation with CNP caused a larger increase in cGMP levels in stretched as well as in nonstretched cells. CONCLUSION: Expression of CNP together with potent NPR-B receptors suggests that in podocytes, CNP may act in an autocrine and/or paracrine manner. Furthermore, in a diabetic kidney, high glucose and mechanical stress may modulate the CNP-dependent cGMP production in podocytes in an opposite manner.

Animals↗
PubMed2005

Angiotensin II receptor blocker inhibits p27Kip1 expression in glucose-stimulated podocytes and in diabetic glomeruli.

BACKGROUND: Diabetic nephropathy is characterized by glomerular and tubular hypertrophy, and angiotensin II receptor blockers (ARBs) are known to prevent renal hypertrophy in diabetic patients. METHODS: To determine the effect of ARB on podocyte p27(Kip1) mRNA and protein expression, podocytes were exposed to 5.6 mmol/L normal glucose or 25 mmol/L high glucose with or without ARB, 10(-7) mol/L L-158,809. For animal studies, streptozotocin-induced diabetic rats were left untreated or were treated with 1 mg/kg/day L-158,809 for 3 months (diabetes mellitus + ARB). Competitive reverse transcription-polymerase chain reaction (RT-PCR), Western blot, immunohistochemistry, and morphometric analyses were performed. RESULTS: p27(Kip1) mRNA and protein expression in podocytes exposed to high glucose and in 3-month diabetic glomeruli were significantly increased (P < 0.01). High glucose significantly increased angiotensin II levels both in cell lysates and in media compared with normal glucose (P < 0.05) and exogenous angiotensin II also increased p27(Kip1) mRNA and protein expression in podocytes. L-158,809 treatment in podocytes inhibited the increase in p27(Kip1) mRNA expression by 84%, and protein expression by 89% (P < 0.05). p27(Kip1) mRNA and protein expression in diabetic + ARB glomeruli were also significantly reduced by 78% and 85%, respectively, compared with diabetic glomeruli (P < 0.01). ARB treatment also significantly ameliorated increased glomerular p27(Kip1) expression in diabetes mellitus as assessed by immunohistochemistry (P < 0.01). The increase in glomerular volume in diabetes mellitus was also inhibited by 81% with ARB treatment (P < 0.05). CONCLUSION: p27(Kip1) mRNA and protein expression were increased in diabetic glomeruli as well as in high glucose-stimulated podocytes, and this increment in p27(Kip1) expression was ameliorated by ARB treatment. These findings indicate that ARB treatment has an additional effect on preventing renal hypertrophy in diabetes mellitus.

Angiotensin II↗
PubMed2005

R-roscovitine (CYC202) alleviates renal cell proliferation in nephritis without aggravating podocyte injury.

BACKGROUND: Cyclin-dependent kinase (CDK) inhibition is a new therapeutic approach to proliferative glomerulonephritides. CDK2 is required for G(1)/S transition and DNA synthesis and is inhibited by CYC202 (R-roscovitine). Since podocytes express CDK2 in nephritis and since loss of podocytes contributes to glomerulosclerosis, the rationale of the present study was to test whether CDK2 inhibition is safe in instances of podocyte injury. METHODS: Rats with passive Heymann nephritis, a model of membranous glomerulonephritis, were treated (day 3 to 30) with vehicle, low (25 mg/kg/day), or high (50 mg/kg/day) doses of CYC202. RESULTS: On day 27, blood pressure was normal in nephritic controls and was dose-dependently reduced by CYC202. Urinary albumin excretion did not differ between the groups on days 9, 16, 23, and 30. To investigate podocyte injury, we assessed the glomerular de novo expression of desmin, which was markedly up-regulated in almost all passive Heymann nephritis glomeruli but was not significantly different between the three groups. No tubulointerstitial de novo expression of desmin or alpha-smooth muscle actin (alpha-SMA), or tubulointerstitial monocyte/macrophage infiltration was noted in any group. Biologic activity of CYC202 was evident in the form of a dose-dependent decrease in the number of glomerular and tubulointerstitial mitotic figures as compared to vehicle alone. Glomerular immunostaining for cyclin D1, a marker for G(0) to G(1) transition, was significantly decreased in CYC202 treated groups at day 9. CONCLUSION: Whereas inhibition of CDKs by CYC202 reduced intrarenal cell proliferation in passive Heymann nephritis it did not aggravate podocyte damage, suggesting that this novel therapeutic approach is safe in renal diseases characterized by podocyte injury.

Animals↗
PubMed2003

Cell biology of the glomerular podocyte.

Glomerular podocytes are highly specialized cells with a complex cytoarchitecture. Their most prominent features are interdigitated foot processes with filtration slits in between. These are bridged by the slit diaphragm, which plays a major role in establishing the selective permeability of the glomerular filtration barrier. Injury to podocytes leads to proteinuria, a hallmark of most glomerular diseases. New technical approaches have led to a considerable increase in our understanding of podocyte biology including protein inventory, composition and arrangement of the cytoskeleton, receptor equipment, and signaling pathways involved in the control of ultrafiltration. Moreover, disturbances of podocyte architecture resulting in the retraction of foot processes and proteinuria appear to be a common theme in the progression of acquired glomerular disease. In hereditary nephrotic syndromes identified over the last 2 years, all mutated gene products were localized in podocytes. This review integrates our recent physiological and molecular understanding of the role of podocytes during the maintenance and failure of the glomerular filtration barrier.

Animals↗
PubMedDate not supplied

The charge for going by foot: modifying the surface of podocytes.

The podocyte is a highly differentiated cell which forms a crucial component of the glomerular filtration barrier. It maintains a large filtration surface through the slit membranes and counteracts the distension of the glomerular basement membrane. The podocyte is covered with an anionic glycocalyx believed to be important in the maintenance of foot process structures, but the mechanisms of the cellular interaction between podocyte charge and its function are not clearly understood. It has been speculated that the charge selectivity of the glomerular barrier is influenced by angiotensin II. In experimental models of glomerular nephropathy neutralization of the polyanionic surface with polycations causes a retraction of podocyte foot processes. The effect of polycations is energy and Ca2+ dependent and results in tyrosine kinase induced phosphorylation of proteins of the foot processes. Charge alterations of the podocyte seem also associated with proteinuria in several human glomerular diseases such as membranous or diabetic nephropathy. The knowledge of the interaction between charge and podocyte function might offer new strategies in the treatment of glomerular diseases.

Animals↗
PubMed2002

Effect of angiotensin II on ANP-dependent guanylyl cyclase activity in cultured mouse and rat podocytes.

The presence of a well-developed contractile apparatus is the feature determining major roles of podocytes in the renal glomeruli. Receptors for a variety of vasoactive hormones are expressed in these cells; however, most of the signaling pathways are still unknown and remain to be elucidated. Angiotensin II (Ang II) and atrial natriuretic peptide (ANP), due to their opposite action, are the major modulators of glomerular filtration. In podocytes, Ang II induces rise in intracellular calcium concentration, whereas ANP stimulates generation of cGMP. The present study was designed to check whether ANP-stimulated cGMP synthesis in podocytes might be affected by Ang II. Cultured rat (RP) and mouse (MP) podocytes were stimulated with ANP, in the absence or presence of Ang II and cyclic GMP was determined by RIA method. Co-incubation of podocytes with ANP and Ang II caused significant (p < 0.01) suppression of ANP-dependent cGMP generation. The effect was prevented by saralasin, an inhibitor of angiotensin receptors. Phorbol-12-myristate-13-acetate (PMA) mimicked, whereas chelerythrine reversed inhibitory effect of Ang II. In conclusion, angiotensin II counteracts ANP-stimulated cGMP synthesis in cultured podocytes. It seems likely that the protein kinase C pathway is involved in this effect.

Angiotensin II↗
PubMed2002

Transcriptional induction of slit diaphragm genes by Lmx1b is required in podocyte differentiation.

LMX1B encodes a LIM-homeodomain transcription factor. Mutations in LMX1B cause nail-patella syndrome (NPS), an autosomal dominant disease with skeletal abnormalities, nail hypoplasia, and nephropathy. Expression of glomerular basement membrane (GBM) collagens is reduced in Lmx1b(-/-) mice, suggesting one basis for NPS nephropathy. Here, we show that Lmx1b(-/-) podocytes have reduced numbers of foot processes, are dysplastic, and lack typical slit diaphragms, indicating an arrest in development. Using antibodies to podocyte proteins important for podocyte function, we found that Lmx1b(-/-) podocytes express near-normal levels of nephrin, synaptopodin, ZO-1, alpha3 integrin, and GBM laminins. However, mRNA and protein levels for CD2AP and podocin were greatly reduced, suggesting a cooperative role for these molecules in foot process and slit diaphragm formation. We identified several LMX1B binding sites in the putative regulatory regions of both CD2AP and NPHS2 (podocin) and demonstrated that LMX1B binds to these sequences in vitro and can activate transcription through them in cotransfection assays. Thus, LMX1B regulates the expression of multiple podocyte genes critical for podocyte differentiation and function. Our results indicate that reduced levels of proteins associated with foot processes and the glomerular slit diaphragm likely contribute, along with reduced levels of GBM collagens, to the nephropathy associated with NPS.

Animals↗
PubMed2003

DNA damage is a novel response to sublytic complement C5b-9-induced injury in podocytes.

In response to Ab-complement-mediated injury, podocytes can undergo lysis, apoptosis, or, when exposed to sublytic (<5% lysis) amounts of C5b-9, become activated. Following the insertion of sublytic quantities of C5b-9, there is an increase in signaling pathways and growth factor synthesis and release of proteases, oxidants, and other molecules. Despite an increase in DNA synthesis, however, sublytic C5b-9 is associated with a delay in G(2)/M phase progression in podocytes. Here we induced sublytic C5b-9 injury in vitro by exposing cultured rat podocytes or differentiated postmitotic mouse podocytes to Ab and a complement source; we also studied the passive Heymann nephritis model of experimental membranous nephropathy in rats. A major finding was that sublytic C5b-9-induced injury caused an increase in DNA damage in podocytes both in vitro and in vivo. This was associated with an increase in protein levels for p53, the CDK inhibitor p21, growth-arrest DNA damage-45 (GADD45), and the checkpoint kinases-1 and -2. Sublytic C5b-9 increased extracellular signal-regulated kinase-1 and -2 (ERK-1 and -2), and inhibiting ERK-1 and -2 reduced the increase in p21 and GADD45 and augmented the DNA damage response to sublytic C5b-9-induced injury. These results show that sublytic C5b-9 induces DNA damage in vitro and in vivo and may explain why podocyte proliferation is limited following immune-mediated injury.

Animals↗
PubMed1990

A cytochemical study of glycocalyx and the membrane cholesterol of rat glomerular podocytes.

In order to elucidate the cytochemical properties of rat podocyte's membranes, the authors studied the constituents and distribution of glycocalyx and membrane cholesterol. Chromic-phosphotungstic acid (Cr-PTA) stain combined with enzyme digestive tests was used for the glycocalyx analysis. A digitonin fixation method was applied for the detection of membrane cholesterol. On the whole surface of podocytes, glycocalyx showed a strongly positive reaction to Cr-PTA. In normal rats, the reactivity on the urinary surface above the slit membrane of the podocyte foot processes was decreased after treatments with neuraminidase, hyaluronidase and heparitinase. The reactivity on the basal surface below the slit membrane disappeared only after treatment with chondroitinase ABC. In Puromycin Aminonucleoside nephrosis (PAN) rats, the foot processes were effaced extensively. Though a highly positive reactivity of Cr-PTA was observed on the urinary surface of the podocytes, the basal surface reacted weakly. The positive reaction of the urinary surface was not affected by the treatments with neuraminidase, hyaluronidase and heparitinase, but the weak reaction of the basal surface disappeared completely through chondroitinase ABC treatment. The distribution of membrane cholesterol was clearly revealed by the digitonin fixation method, showing digitonin cholesterol complexes of localized trilamellar structures. In normal rat podocytes the complexes were found on the urinary surface, with only a few on the basal surface. In PAN rats the complexes were seldom noticed either on the urinary or basal surfaces. The heterogeneous distribution of glycocalyx and membrane cholesterol seen in normal rat podocytes are changed remarkably under nephrotic condition.

Animals↗
PubMed2005

Statins prevent oxidized LDL-induced injury of glomerular podocytes by activating the phosphatidylinositol 3-kinase/AKT-signaling pathway.

The injury of podocytes is associated with alterations of the glomerular size-selective barrier to proteins. In this study, oxidized LDL (oxLDL) but not native LDL induced apoptosis in human cultured podocytes and reduced Akt activity and P-Akt/Akt ratio. Moreover, oxLDL-induced redistribution and loss of nephrin, an adhesion molecule specific for the glomerular slit diaphragm. Nephrin reduction was preceded by inhibition of nephrin tyrosine phosphorylation and of its association with p85 phosphatidylinositol 3-kinase (PI3K). Moreover, three different statins, mevastatin, pravastatin, and simvastatin, inhibited in a dose-dependent manner apoptosis and loss of nephrin induced by oxLDL by stimulating Akt activity. In addition, simvastatin significantly increased the expression of nephrin protein and mRNA by podocytes. The protective effects of statins were blocked by treatment of podocytes with two unrelated pharmacologic inhibitors of PI3K, LY294002 and wortmannin, suggesting a role for PI3K, and by mevalonate, indicating dependency on HMG-CoA reductase activity. Statins directly stimulated Akt phosphorylation ad activity. Finally, oxLDL induced a retraction of cultured podocytes and an increase in the albumin diffusion across their monolayer that was inhibited by treatment with statins. In conclusion, statins reduced the oxLDL-induced apoptosis and loss of nephrin in glomerular podocytes. The statin-induced Akt activation may protect from the loss of nephrin by an inhibition of its redistribution and shedding and by a stimulation of its synthesis. These data provide a rationale for the anti-proteinuric effect of statins.

Apoptosis↗
PubMed2005

Sam68-like mammalian protein 2, identified by digital differential display as expressed by podocytes, is induced in proteinuria and involved in splice site selection of vascular endothelial growth factor.

Podocytes, the glomerular epithelial cells of the kidney, share important features with neuronal cells. In addition to phenotypical and functional similarities, a number of gene products have been found to be expressed exclusively or predominantly by both cell types. With the hypothesis of a common transcriptome shared by podocytes and neurons, digital differential display was used to identify novel podocyte-expressed gene products. Comparison of brain and kidney cDNA libraries with those of other organs identified Sam68-like mammalian protein 2 (SLM-2), a member of the STAR family of RNA processing proteins, as expressed by podocytes. SLM-2 expression was found to be restricted in the kidney to podocytes. In proteinuric diseases, SLM-2, a known regulator of neuronal mRNA splice site selection, was found significantly upregulated on mRNA and protein levels. Knockdown of SLM-2 by short interfering RNA in podocytes was performed to evaluate its biologic role. RNA splicing of vascular endothelial growth factor (VEGF), a key regulator of the filtration barrier and expressed as functionally distinct splice isoforms, was evaluated. VEGF(165) expression was found to be reduced by 25% after SLM-2 knockdown. In vivo, the glomerular expression of SLM-2 correlated with the mRNA levels of VEGF(165). This study demonstrates the power of digital differential display to predict cell type-specific gene expression by hypothesis-driven analysis of tissue cDNA libraries. SLM-2-dependent VEGF splicing indicates the importance of mRNA splice site selection for glomerular filtration barrier function.

Animals↗
PubMed2002

A conditionally immortalized human podocyte cell line demonstrating nephrin and podocin expression.

Recent molecular insights have established the podocyte as a key component of the glomerular filtration barrier, and hence an important common pathway in proteinuric diseases. A conditionally immortalized human podocyte cell line has been developed by transfection with the temperature-sensitive SV40-T gene. These cells proliferate at the "permissive" temperature (33 degrees C). After transfer to the "nonpermissive" temperature (37 degrees C), they entered growth arrest and expressed markers of differentiated in vivo podocytes, including the novel podocyte proteins, nephrin, podocin, CD2AP, and synaptopodin, and known molecules of the slit diaphragm ZO-1, alpha-, beta-, and gamma-catenin and P-cadherin. The differentiation was accompanied by a growth arrest and the upregulation of cyclin-dependent kinase inhibitors, p27 and p57, as well as cyclin D(1), whereas cyclin A was downregulated. These data are consistent with cell cycle protein expression during podocyte maturation in vivo. In conclusion, the development of this cell line provides a new tool in the study of podocyte biology, which will enable accurate assessment of the behavior of these complex cells in health and disease.

Biomarkers↗
PubMed1998

Catecholamines modulate podocyte function.

The aim of this study was to investigate the influence of adrenoceptor agonists on the intracellular calcium activity ([Ca2+]i), membrane voltage (Vm), and ion conductances (Gm) in differentiated mouse podocytes. [Ca2+]i was measured by the Fura-2 fluorescence method in single podocytes. Noradrenaline and the alpha 1-adrenoceptor agonist phenylephrine induced a reversible and concentration-dependent biphasic increase of [Ca2+]i in podocytes (EC50 approximately 0.1 microM for peak and plateau), whereas the alpha 2-adrenoceptor agonist UK 14.304 did not influence [Ca2+]i. The [Ca2+]i response induced by noradrenaline was completely inhibited by the alpha 1-adrenoceptor antagonist prazosin (10 nM). In a solution with a high extracellular K+ (72.5 mM), [Ca2+]i was unchanged and the [Ca2+]i increase induced by noradrenaline was not inhibited by the L-type Ca2+ channel blocker nicardipine (1 microM). Vm and Gm were examined with the patch-clamp technique in the slow whole-cell configuration. Isoproterenol, phenylephrine, and noradrenaline depolarized podocytes and increased Gm. The order of potency for the adrenoceptor agonists was isoproterenol (EC50 approximately 1 nM) > noradrenaline (EC50 approximately 0.3 microM) > phenylephrine (EC50 approximately 0.5 microM). The beta 2-adrenoceptor antagonist ICI 118.551 (5 to 100 nM) inhibited the effect of isoproterenol on Vm. Stimulation of adenylate cyclase by forskolin mimicked the effect of isoproterenol on Vm and Gm (EC50 approximately 40 nM). Isoproterenol induced a time- and concentration-dependent increase of cAMP in podocytes. The effect of isoproterenol was unchanged in the absence of Na+ or in an extracellular solution with a reduced Ca2+ concentration, whereas it was significantly increased in an extracellular solution with a reduced Cl- concentration (from 145 to 32 mM). The data indicate that adrenoceptor agonists regulate podocyte function: They increase [Ca2+]i via an alpha 1-adrenoceptor and induce a depolarization via a beta 2-adrenoceptor. The depolarization is probably due to an opening of a cAMP-dependent Cl- conductance.

Adrenergic alpha-Agonists↗
PubMed2002

Podocyte number in normotensive type 1 diabetic patients with albuminuria.

We estimated glomerular cell number in 50 normotensive type 1 diabetic patients with raised albumin excretion rate (AER) and investigated any change after 3 years in a subgroup of 16 placebo-treated patients. Biopsies from 10 normal kidney donors were used as controls. Mesangial and endothelial cell number was increased in the 50 diabetic patients at the start of the study compared with control subjects. There was no difference in podocyte number. Glomerular volume was increased in diabetic patients, but surface area of glomerular basement membrane (GBM) underlying the podocytes did not differ between groups. AER correlated positively with mesangial cell number in microalbuminuric patients (r = 0.44, P = 0.012) and negatively with podocyte number in proteinuric patients (r = -0.48, P = 0.040). In the 16 placebo-treated patients, glomerular volume increased after 3 years owing to matrix accumulation and increased GBM surface area. Although overall cell number did not differ significantly from baseline, the decrease in podocyte number during follow-up correlated with AER at follow-up (r = -0.72, P = 0.002). In conclusion, cross-sectional analysis of podocyte number in type 1 diabetic patients with raised AER but normal blood pressure shows no significant reduction compared with nondiabetic control subjects. Longitudinal data provide evidence for an association between podocyte loss and AER, but whether cellular changes are a response to, a cause of, or concomitant with the progression of nephropathy remains uncertain.

Adult↗
PubMed2003

Is podocyte injury relevant in diabetic nephropathy? Studies in patients with type 2 diabetes.

Podocyte structural changes have been suggested to be involved in the pathogenesis of albuminuria in diabetes. We evaluated podocytes density, number, and structure in 67 white patients with type 2 diabetes: 21 normoalbuminuric (NA), 23 microalbuminuric (MA), and 23 proteinuric (P). Kidney function and biopsy studies were performed; 20 kidney donors served as control subjects. Electron microscopic morphometric analysis was used to estimate numerical density of podocytes per glomerulus [Nv(epi/glom)], filtration slit length density per glomerulus (FSLv/glom), and foot process width (FPW). The number of podocytes per glomerulus (Epi N/glom) was obtained by multiplying Nv(epi/glom) by mean glomerular volume. Nv(epi/glom) was significantly decreased in all type 2 diabetic groups compared with control subjects and was lower in MA and P than in NA (P < 0.0001, ANOVA). Epi N/glom was lower in MA and P patients compared with control subjects (P < 0.002, ANOVA); however, there were no significant differences among the type 2 diabetic groups. In addition, MA and P had decreased FSLv/glom and increased FPW compared with NA (P < 0.005 for both, ANOVA). The albumin excretion rate was inversely related to Nv(epi/glom) and FSLv/glom and directly to FPW (P < 0.0005 for all), whereas there was no correlation with Epi N/glom. In conclusion, changes in podocyte structure and density occur since the early stages of diabetic nephropathy and might contribute to increasing albuminuria in type 2 diabetic patients. These findings also suggest that in white type 2 diabetic patients, the density of podocytes may be functionally more relevant than the absolute number.

Aged↗