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PubMed2003

Glomerular podocytes possess the synaptic vesicle molecule Rab3A and its specific effector rabphilin-3a.

Several recent studies have focused on similarities between glomerular podocytes and neurons because the two cells share a specialized cytoskeletal organization and several expression-restricted proteins, such as nephrin and synaptopodin. In neurons, the small guanosine triphosphatase Rab3A and its effector rabphilin-3A form a complex required for the correct docking of synaptic vesicles to their target membrane. Because rabphilin-3A binds in neurons to cytoskeletal proteins also important for podocyte homeostasis, and the complex rabphilin-3A-Rab3A has been demonstrated in neurons and neuroendocrine cells, the aim of our work was to investigate their possible expression and regulation in podocytes. Normal kidneys from mouse, rat, and human were studied by immunohistochemistry, Western blotting, and reverse transcriptase-polymerase chain reaction to evaluate the expression of Rab3A and rabphilin-3A. Double-staining immunohistochemistry and immunogold electron microscopy were then used to precisely localize the two proteins at the cellular and subcellular levels. Rab-3A and rabphilin-3A regulations in disease were then analyzed in growth hormone-transgenic mice, a well established model of focal and segmental glomerulosclerosis, and in human biopsies from proteinuric patients. Our results demonstrated that rabphilin-3A and Rab3A are present in normal mouse, rat, and human kidneys, with an exclusively glomerular expression and a comma-like pattern of positivity along the glomerular capillary wall, suggestive for podocyte staining. Co-localization of both molecules with synaptopodin confirmed their presence in podocytes. By immunogold electron microscopy both proteins were found around vesicles contained in podocyte foot processes. Their expression was increased in growth hormone-transgenic mice compared to their wild-type counterpart, and in a subset of biopsies from proteinuric patients. Our data, demonstrating the presence of two synaptic proteins in podocytes, further supports similarities between cytoskeletal and vesicular organization of podocytes and neurons. The altered expression observed in mouse and human proteinuric diseases suggests a possible role for these molecules in glomerulopathies.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Variable expression of podocyte-related markers in the glomeruloid bodies in Wilms tumor.

Several podocyte-related markers are organized to express in glomerular differentiation. However, whether expression of them is virtually synchronized and a reliable indicator of the state of differentiation is unknown. The present study investigated, by immunohistochemistry, the divergent expression of several podocyte markers in the improperly differentiated glomeruloid bodies from four cases of Wilms tumors. The glomeruloid bodies were classified into immature (IGB) or mature forms (MGB) based on morphology and epithelial features. Podocytes in IGB expressed WT1, synaptopodin, podocalyxin, and nephrin, and their expression was stronger in MGB. In contrast, Pax2 was strong in IGB and diminished in MGB. p27 was first expressed in MGB. The expression pattern in each molecule mimics normal glomerulogenesis. Podocytes in MGB showed persistent expression of bcl-2 and cytokeratin with synaptopodin, podocalyxin, and nephrin by serial section, a finding unusual for normal glomerulogenesis. Moreover, parietal cells in MGB also occasionally expressed these podocyte markers. The ultrastructure revealed that podocytes in MGB showed tight junctions without foot process formations, which indicated incomplete differentiation. These results suggest that a set of podocyte differentiation markers are occasionally diversely expressed, and raise the possibility that expression of these markers is insufficient to determine the state of terminal differentiation in podocytes.

Biomarkers, Tumor↗
PubMed1998

Detection of multiple vascular endothelial growth factor splice isoforms in single glomerular podocytes.

Glomerular podocytes are major determinants of filtration permselectivity in the glomerulus. Although the molecular mechanisms determining the characteristics of the glomerular filtration unit are incompletely understood, vascular endothelial growth factor (VEGF) has been implicated. To analyze this process in situ, we established a method that allows exploration of in vivo mRNA expression of podocytes using single-cell reverse transcriptase-polymerase chain reaction (RT-PCR). Microdissected mouse glomeruli were held in a patch-clamp apparatus, and single podocytes were harvested by aspiration. After lysis, the cells were reverse transcribed, and PCR was performed (45 cycles). The podocyte nature of the material was confirmed by detection of podocyte-specific mRNA (glomerular epithelial protein 1 and Wilms' tumor protein 1). Using specific oligonucleotide primers, VEGF was detected in mRNA obtained from renal cortex, single microdissected glomeruli, cultured murine podocytes, and single podocytes in situ. All cells examined expressed three VEGF isoforms (121, 165, and 189). These differ in their capacity for binding to extracellular matrix and could have different potencies regulating glomerular endothelial permeability. Our approach should allow a semiquantitative, isoform-specific evaluation of VEGF mRNA expression in podocytes during nephrogenesis and in glomerular disease.

Animals↗
PubMed2002

Significance of early phenotypic change of glomerular podocytes detected by Pax2 in primary focal segmental glomerulosclerosis.

In primary focal segmental glomerulosclerosis (FSGS), phenotypic alteration of podocytes is important for the development of cellular lesions (CLs), which precede glomerular scar formation. WT1 and Pax2 are transcription factors involved in kidney development and phenotypic regulation of glomerular epithelial cells. However, the role of WT1 and Pax2 in the development of CLs in primary FSGS is unclear. Using immunohistochemistry, the expression of WT1, Pax2, and cytokeratin (CK), an epithelial marker never found in normal podocytes, was examined in 35 biopsy samples of primary FSGS. Segmental lesions were categorized as: (1) classic segmental scar (CS), (2) CL, and (3) monolayer epithelial (ME) lesion. In normal glomeruli, WT1 was strongly positive in podocytes and weakly positive in parietal epithelium of Bowman's capsule. Pax2 was strongly positive in parietal epithelium of Bowman's capsule, but never expressed in podocytes. Expression of WT1, Pax2, and CK was scantly positive in CSs. WT1 expression was decreased in CLs compared with unaffected podocytes, but Pax2 and CK were strongly expressed in CLs and podocytes of morphologically unaffected tufts in cases with CLs. WT1 expression was strong, as well as Pax2 and CK, in ME lesions. Clinically, urinary protein levels were significantly greater, and the interval from clinical onset to biopsy was significantly shorter in patients with CLs. These results suggest that re-expression of Pax2 in podocytes resulting in phenotypic change to a different epithelial form is one of the important changes for the development of CLs and ME lesions. Alteration from WT1 to Pax2 in podocytes may have an important role in the initiation of glomerular injury in primary FSGS.

Aged↗
PubMed2001

Pioglitazone reduces urinary podocyte excretion in type 2 diabetes patients with microalbuminuria.

In various renal diseases, including diabetic nephropathy, detection of podocytes in the urine indicates severe injury to podocytes in the glomeruli. Pioglitazone is a newly developed antidiabetic agent that attenuates insulin resistance. The aim of the present study was to determine whether pioglitazone affects urinary albumin excretion (UAE) or the number of urinary podocytes or both in type 2 diabetes patients with microalbuminuria. Twenty-eight patients with normotensive type 2 diabetes and microalbuminuria (18 men and 10 women; mean age, 52.5 years) and 30 age-matched normotensive controls (20 men and 10 women; mean age, 51.5 years) were included in the study. Urinary podocytes were detected by immunofluorescence with a monoclonal antibody against podocalyxin. Patients were randomly assigned to 2 groups: a pioglitazone-treatment group (30 mg/day, n = 14) and a placebo group (n = 14). Treatment was continued for 6 months. Podocytes were absent in the urine of healthy controls, but detected in 17 of 28 diabetic patients (60.7%). UAE was reduced from 96.7 +/- 50.5 microg/min to 39.7 +/- 22.9 microg/min (P <.01) in the pioglitazone-treatment group, and the number of urinary podocytes was reduced from 0.9 +/- 1.0 cells/mL to 0.1 +/- 0.2 cells/mL (P <.001). Neither UAE nor the number of urinary podocytes was affected in the placebo group. These data indicate that pioglitazone is effective for reducing UAE and podocyte injury in early-stage diabetic nephropathy.

Albuminuria↗
PubMed1999

Dopamine depolarizes podocytes via a D1-like receptor.

BACKGROUND: Dopamine influences glomerular haemodynamics and dopamine receptors have been demonstrated in the glomerulus, but little is known about the cellular effects of dopamine in glomerular cells. The aim of this study was to investigate the influence of dopamine on the cellular functions of podocytes. METHODS: The effect of dopamine on membrane voltage was investigated in differentiated mouse podocytes. The membrane voltage was measured using the patch clamp technique. Reverse transcribed-polymerase chain reaction (RT-PCR) studies were performed to investigate the expression of dopamine receptor mRNA in mouse glomeruli and podocytes. RESULTS: The addition of dopamine (100 nM-1000 microM) caused a concentration-dependent depolarization of podocytes (EC50 is approximate to 10 microM). Like dopamine, the selective agonist of the D1-like receptor, SKF 82958, depolarized podocytes in a concentration-dependent manner. (EC50 is approximate to 50 microM). SKF 82958 stimulated a time-and concentration-dependent accumulation of cyclic adenosine 3',5'-monophosphate (cAMP) in podocytes (EC50 is approximate to microM). RT-PCR studies with primers derived from mouse sequences amplified mouse mRNA for the D1-like and the D2-like receptor in glomeruli, which were obtained by the sieve technique, whereas only mRNA for the D1-like receptor was detected in cultured mouse podocytes. CONCLUSION: The data indicate that dopamine induces a cAMP-dependent depolarization via a D1-like receptor in podocytes.

Animals↗
PubMed2002

Cadherin and catenin staining in podocytes in development and puromycin aminonucleoside nephrosis.

Podocytes have been shown to express classical cadherins in the early stage of glomerulogenesis, but it remains unclear whether podocytes in normal and pathological conditions express cadherins in the adult stage. To address this question, rat podocytes in the neonate, the adult and in puromycin aminonucleoside (PAN) nephrosis were examined by immunofluorescence microscopy using antibodies against alpha- and beta-catenins and anti-pan-cadherin antibody, and by immunoelectron microscopy using anti-alpha-catenin antibody. In the neonate, all the antibodies reacted with the junctional complex of podocytes in the S-shaped body stage. The staining disappeared during the capillary loop stage, when foot processes and slit diaphragms are formed. In the adult, podocytes were not stained with any of the antibodies, whereas distinct staining with the antibodies was detected in endothelial cells and mesangial cells in the glomerulus. These findings were identical in kidneys of PAN nephrosis; podocytes did not show any significant staining. These results indicate that the composition of intercellular junction molecules of podocytes in the adult is different from that of immature podocytes even under the pathological condition.

Animals↗
PubMed2003

Stra13, a prostaglandin E2-induced gene, regulates the cellular redox state of podocytes.

Podocyte injury is a central mechanism in the pathogenesis of proteinuria. Prostaglandin E2 (PGE2) has been suggested to protect podocytes from cellular injury. Here we investigated whether PGE2-induced gene expression accounts for the protective role of PGE2 in podocytes. Using a suppressive-subtractive hybridization method, we isolated a differentially expressed clone that was identified as Stra13, a recently described retinoic acid-inducible gene. PGE2, forskolin, and retinoic acid induced a time-dependent up-regulation of Stra13 mRNA and protein expression in podocytes. To test the function of Stra13 in podocytes, Stra13 was overexpressed by using retroviral gene transfer. Compared with control cells, cells overexpressing Stra13 showed markedly reduced NADPH-dependent superoxid anion generation. Furthermore, expression of heme oxygenase 1 (HO-1) was increased in podocytes overexpressing Stra13. HO-1 plays an important protective role in the defense against reactive oxygen species (ROS). After stimulation with exogenous ROS, Stra13-overexpressing podocytes were more resistant to oxidative stress than were control cells. Our data indicate that Stra13 may play an important protective role against oxidative stress in podocytes. ROS are involved in the pathogenesis of glomerular inflammation in several forms of glomerulonephritis. Therefore, knowledge about protective mechanisms may provide insight into new therapeutic strategies for glomerulopathies.

Animals↗
PubMed2003

IFN-inducible protein-10 has a differential role in podocyte during Thy 1.1 glomerulonephritis.

IFN-inducible protein-10 (IP-10/CXCL10) is a potent chemoattractant for activated T lymphocytes and was recently reported to have several additional biologic activities. In this study, the expression and the function in normal glomeruli and in Thy1.1 glomerulonephritis (GN) were investigated. The expression of IP-10 was detected in normal rat glomeruli mainly in the podocyte. The expression of IP-10 was also detected on the cultured podocyte. The IP-10 expression was elevated at the early phase of Thy1.1 GN. The double staining immunofluorescence study clearly demonstrated that the elevated expression of IP-10 was mostly detected in the podocyte and very partly in mesangial area. A receptor for IP-10, CXCR3, showed similar expression patterns to that of IP-10. Expressions of neither of IP-10 nor of CXCR3 were detected on the inflammatory cells. For elucidating the role of IP-10, the blocking study was carried out with monoclonal anti-IP-10 antibody. The monoclonal anti-IP-10 antibody treatment decreased the expression of IP-10 and podocyte-associated proteins such as nephrin and podocin that are reported to be essential for maintaining the podocyte function (IP-10, 53.0% to control; nephrin, 43.5%; podocin, 60.4%). The findings indicated that the anti-IP-10 treatment disturbed the podocyte function. The anti-IP-10 treatment given to the rats with Thy1.1 nephritis exacerbated proteinuria, mesangiolysis, and matrix expansion. Collectively, the findings indicated that IP-10 plays a role in maintaining the podocyte function. Also, the findings suggested that anti-IP-10 treatment exacerbated the glomerular alterations in Thy1.1 GN by disturbing the podocyte function.

Animals↗
PubMed2004

Stable expression of nephrin and localization to cell-cell contacts in novel murine podocyte cell lines.

BACKGROUND: Cell culture of podocytes has become an indispensable tool in the study of podocyte biology. To date, however, podocyte cell lines with stable expression of the crucial slit diaphragm protein nephrin and localization of nephrin to cell-cell contacts are not available. METHODS: Conditionally immortalized cells were grown from isolated glomeruli of mice, harboring the temperature-sensitive SV40 large T antigen. About 60 clonal cell lines were generated by limiting dilution. RESULTS: Among 30 Wilm's tumor (WT)-1- and podocalyxin-positive cell clones, two cell clones stably expressed nephrin as assessed by reverse transcription-polymerase chain reaction (RT-PCR), Northern and Western blotting, and immunofluorescence. In addition, expression of the following podocyte proteins was demonstrated: NEHP1, FAT, P-cadherin, podocin, CD2AP, ZO-1 (alpha(-) isoform), Lmx1b, podoplanin, synaptopodin, cortactin, and vimentin. The nephrin-positive podocyte cell lines formed a monolayer with abundant cell-cell contacts. Transmission electron microscopy revealed formation of primitive foot process-like interdigitations and slit diaphragm-like junctions. Nephrin colocalized with F-actin at cell-cell contacts as demonstrated by immunofluorescence. Intriguingly, nephrin and actin-associated proteins (synaptopodin, CD2AP, and cortactin) were recruited to and accumulated at the entire cell margin only in confluent cells, but not in dispersed cells. CONCLUSION: We present novel murine podocyte cell lines with stable expression of nephrin and abundant formation of cell-cell contacts, possessing several features of in situ podocyte cell-cell contacts. Furthermore, our data suggest that the accumulation of certain proteins in podocyte foot processes is linked to formation of cell-cell contacts.

Animals↗
PubMed2004

Regulation of vascular permeability factor/vascular endothelial growth factor (VPF/VEGF-A) expression in podocytes.

BACKGROUND: Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF-A) is expressed constitutively in the adult glomerular podocytes at high levels; however, the regulation of its production is unclear. Recent data from podocyte-specific knockout mice suggest that VPF/VEGF-A is critical for the proper maintenance of glomerular filtration barrier and the glomerular endothelial fenestrae. We hypothesized that the glomerular basement membrane (GBM) matrix-podocyte interaction may play a role in the constitutive expression of VPF/VEGF-A in the adult glomerulus. METHODS: VPF/VEGF-A mRNA levels in a human podocyte cell line grown in the presence of various extracellular matrices were quantitated by real-time polymerase chain reaction (PCR) experiments. VPF/VEGF-A protein levels in the culture supernatant from the same conditions were measured by enzyme-linked immunosorbent assay (ELISA). Promoter activity of VPF/VEGF-A gene in these cells was performed by transfecting full length (2.6 kb) VPF/VEGF-A promoter, which is fused with luciferase reporter gene. Immunoprecipitation and Western blot experiments were carried out in order to detect the association of hypoxia-inducible factor-alpha (HIF-alpha) and p300 in podocyte cells. RESULTS: In this study, we provide preliminary evidence that signaling through the extracellular matrix proteins and, in particular, laminin and its receptor alpha(3)beta(1) integrin may regulate VPF/VEGF-A production in cultured podocytes in vitro. We also present data that increased activity of the transcription factor HIF-alphas in podocyte is not related to hypoxia and may lead to up-regulation of VPF/VEGF-A transcription. The classical type protein kinase C (PKC) may be a potential intermediate signaling molecule in this event. CONCLUSION: These data suggest a novel nonhypoxic regulation of VPF/VEGF-A production in the glomerulus of the kidney during physiologic states. These observations may form the basis of more elaborate studies that will finally provide the detailed signaling pathway for VPF/VEGF-A synthesis in podocytes and will help our understanding of the pathogenesis of various VPF/VEGF-A-related diseases in the glomerulus of the kidney.

Basic Helix-Loop-Helix Proteins↗
PubMed2005

Differential proteomic analysis of proteins induced by glucocorticoids in cultured murine podocytes.

BACKGROUND: The glomerular podocyte is the kidney cell most affected during the development of nephrotic syndrome, and mutations in podocyte proteins are responsible for a variety of inherited forms of nephrotic syndrome. Although glucocorticoids are a primary treatment for nephrotic syndrome, neither their target cell nor mechanism of action are known. In order to describe the proteome of the podocyte, and to identify podocyte proteins whose expression is altered by glucocorticoids, we performed a differential proteomic analysis of control and dexamethasone-treated cultured murine podocytes. METHODS: Podocyte proteins were separated by two-dimensional-polyacrylamide gel electrophoresis (PAGE) and identified by matrix-assisted laser desorption time-of-flight (MALDI-TOF) mass spectrometry and peptide fingerprinting. Comparisons of stained two-dimensional-PAGE separations were used to identify proteins whose expression was altered by treatment with the glucocorticoid dexamethasone, and these results were confirmed by quantitative Western blotting. RESULTS: A total of 106 protein spots yielded MALDI-TOF results, and 92 were identified by protein fingerprinting. Of the 88 unique proteins and four protein isoforms identified, six proteins were found whose expression was altered by dexamethasone. The proteome of cultured murine podocytes is particularly rich in actin cytoskeletal proteins and proteins involved in responses to cellular stress. The change in expression of three proteins [ciliary neurotrophic factor (CNTF), alphaB-crystallin, and heat shock protein 27 (hsp27)] was confirmed by quantitative Western blotting. CONCLUSION: Three proteins with known roles in protecting cells from injury were up-regulated by dexamethasone, demonstrating that glucocorticoids exert a direct effect on cultured podocytes resulting in changes in the expression of proteins with potential relevance to the therapeutic action of glucocorticoids in diseases such as nephrotic syndrome.

Animals↗
PubMed2005

Insulin-like growth factors inhibit podocyte apoptosis through the PI3 kinase pathway.

BACKGROUND: Abnormal podocyte development and progressive podocyte injury have been implicated in a number of human kidney diseases. Factors necessary for regulating development and maintenance of this cell type are only beginning to emerge. METHODS: To study the role of the insulin-like growth factor (IGF) system in regulating podocyte survival, we induced human fetal podocytes to undergo apoptosis. We demonstrated a significant increase in apoptosis when these cells were incubated in the presence of etoposide, as measured by DNA fragmentation and nuclear membrane condensation and blebbing. RESULTS: Podocyte apoptosis was reduced to control levels when the cells were coincubated in the presence of IGF-1. We showed that the protective effect of IGFs in this cell type was mediated through the activation of the phosphatidylinositol 3'-kinase (PI3K) pathway. IGF-1 stimulation resulted in the formation of the insulin receptor substrate (IRS)-1-p85 complex, an increase in PI3 kinase activity, and activation of protein kinase B (AKT/PKB) and the bcl-2 family member bad. Incubation of the podocytes with inhibitors of the PI3 kinase pathway resulted in a loss of this IGF-1 protective effect. CONCLUSION: These data demonstrate an important role for the IGF system in fetal podocyte survival in vitro, and suggest potential mediators to slow or alleviate the loss or damage of the podocyte in progressive renal disease.

Apoptosis↗
PubMed2003

Urinary excretion of viable podocytes in health and renal disease.

The loss of glomerular visceral epithelial cells (podocytes) has been associated with the development of glomerular sclerosis and loss of renal function. Viability of podocytes recovered from urine of subjects with glomerular disease and of healthy controls was investigated by propidium iodide exclusion and TUNEL staining. Podocyte loss was quantified by cytospin. The growth behavior in culture of urinary cells and their expression of specific markers were examined. The majority of urinary podocytes are viable, although apoptosis occurs in about one-half of the cells. Patients with active glomerular disease excreted up to 388 podocytes/mg creatinine, whereas healthy controls and patients with quiescent disease generally excreted <0.5 podocytes/mg creatinine. The identity of cultured cells was confirmed by their morphology, growth behavior, and expression of podocyte-specific markers. The difference in growth behavior between healthy controls and subjects with active glomerular disease suggests that in active disease viable podocytes detach from the glomerular tuft due to local environmental factors rather than defects in the podocytes per se, whereas in healthy individuals mostly senescent podocytes are shed.

Adolescent↗
PubMed2000

Roles of the podocyte in glomerular function.

The podocyte is the most differentiated cell type in the glomerulum, which forms a crucial component of the glomerular filtration barrier. It has been assumed that podocyte foot processes counteract the elastic force of the glomerular basement membrane and that vasoactive hormones may regulate the contractile state of their foot processes and thereby modulate the ultrafiltration coefficient K(f). Podocyte damage leads to proteinuria, and podocyte injury occurs in many glomerular diseases, which may progress to chronic renal failure. The understanding of the regulation of physiological properties of the podocyte and the mechanisms of its cellular response to injury may thus provide a clue to the understanding of the pathogenesis of proteinuria and glomerular diseases. In the past it was difficult to study cellular functions in this cell type, because of its unique anatomic location and the difficulty in characterizing podocytes in cell culture. However, recent advances in physiological, molecular biological, and cell culture techniques have increased the knowledge of the role of the podocyte in glomerular function. The present review attempts to outline new aspects of podocyte function in the glomerulum.

Adenosine Triphosphate↗
PubMedDate not supplied

The urinary podocyte as a marker for the differential diagnosis of idiopathic focal glomerulosclerosis and minimal-change nephrotic syndrome.

BACKGROUND/AIMS: Detection of podocytes in the urine sediment of children indicates that severe podocyte injury occurred in the glomerulus. Focal glomerulosclerosis (FGS) and minimal-change nephrotic syndrome (MCNS) are kidney diseases characterized by massive proteinuria. The aim of the present study was to determine whether urinary podocytes can be detected in patients with idiopathic FGS or MCNS and whether immunosuppression therapy alters these cells. METHODS: Twenty patients with MCNS (nephrotic stage, n = 12; remission stage, n = 8), 15 patients with FGS and 20 healthy controls were included in the present study. Urinary podocytes were stained by immunofluorescence. All patients with MCNS at the nephrotic stage received prednisolone for 6 months, and all patients with FGS received some form of immunosuppression therapy including prednisolone, cyclophosphamide or mizoribine for 12 months. RESULTS: The 12 nephrotic-stage MCNS patients achieved remission after treatment. Seven of the 15 FGS patients also achieved remission, but the other 8 remained in the nephrotic stage. Urinary podocytes were not detected in any patient with MCNS nor were they detected in healthy controls. Urinary podocytes were detected in all FGS patients (mean, 4.2 cells/ml) before treatment and the number of cells decreased in the 7 patients who achieved remission. The number of podocytes was unchanged in the other 8 patients even after treatment. CONCLUSION: Urinary podocytes may be a useful diagnostic indicator for differentiation between FGS and MCNS. These cells may also mark disease progression in cases of FGS.

Adult↗
PubMedDate not supplied

Effects of angiotensin-converting enzyme inhibitor, angiotensin II receptor antagonist and calcium antagonist on urinary podocytes in patients with IgA nephropathy.

The urinary podocyte is postulated to be a marker for estimation of the severity of active glomerular injury and a predictor of disease progression in children with glomerulonephritis. Non-dihydropyridine calcium antagonist, including verapamil, reduce proteinuria to an extent similar to that of the angiotensin-converting enzyme inhibitor (ACEI), including trandolapril, but to a greater extent than other antihypertensives. Angiotensin (Ang) II receptor antagonists, including candesartan cilexetil, show potent and long-term preventive effects against the progression of renal injury. The aim of the present study is to assess whether verapamil, trandolapril and candesartan cilexetil affect proteinuria and urinary podocytes in patients with IgA nephropathy. Thirty-two normotensive patients aged 18-54 years with biopsy-proven IgA nephropathy, nonnephrotic proteinuria (1-3 g/day), and normal renal function (creatinine clearance >80 ml/min) were studied. Twenty patients with diffuse mesangial proliferative glomerulonephritis (non-IgA PGN) and 20 healthy controls were also included in this study. The number of urinary podocytes in patients with advanced IgA nephropathy (n = 16) was significantly higher than that in patients with the disease in the mild stage (n = 16) (p < 0.01) or in patients with non-IgA PGN (p < 0.01). Urinary podocytes were not detected in healthy controls. The 32 patients with IgA nephropathy were randomly divided into four treatment groups: those treated with verapamil (120 mg/day, n = 8); those treated with trandolapril (2 mg/day, n = 8); those treated with candesartan cilexetil (8 mg/day, n = 8), and those given a placebo (n = 8). Treatment continued for 3 months. Antiproteinuric response in the trandolapril group was similar to that in the candesartan cilexetil group (-38 vs. -40%). The action of trandolapril or candesartan cilexetil was greater than that of verapamil (p < 0.01). Reduction in the number of urinary podocytes from baseline was significantly greater in patients treated with trandolapril or candesartan cilexetil than in patients treated with verapamil (p < 0.01). However, there was no difference between patients treated with trandolapril and those treated with candesartan cilexetil. Proteinuria and urinary podocytes were unaffected in the placebo group. These data suggest that urinary podocytes may be a marker of disease activity in adult patients with IgA nephropathy and that trandolapril and candesartan cilexetil are more effective than verapamil in reducing the number of podocytes.

Adult↗
PubMed2001

Expression and signaling of parathyroid hormone-related protein in cultured podocytes.

Podocyte function appears to be regulated by vasoactive factors. In vivo podocytes express parathyroid hormone-related protein (PTHrP), the N-terminal fragment of which has vasoactive properties. Since the signaling pathway(s) of PTHrP(1-36) are unknown in podocytes, differentiated cells of a conditionally immortalized mouse podocyte cell line were studied. Gene expression of PTHrP and the PTH/PTHrP receptor was investigated by RT-PCR; protein distribution of PTHrP was examined by immunofluorescence. Accumulation of cAMP was determined by an enzyme immunoassay; [Ca2+]i was measured by fura-2 ratio imaging. PTHrP and PTH/PTHrP receptor mRNA was detected in differentiated podocytes. Immunoreactive PTHrP exhibited a granular distribution in the cytoplasm of differentiated podocytes. With regard to the signaling pathway(s) of PTHrP(1-36), a concentration-dependent increase of cAMP levels with an EC50 value of 4 +/- 2 nM was found. PTHrP(1-36) (1 microM) increased cAMP levels 5.5 +/- 1.1-fold above baseline as compared with a 25.4 +/- 4.2-fold increase in response to forskolin (10 microM). The PTH/PTHrP receptor antagonist PTHrP(7-34) significantly diminished the PTHrP(1-36)-induced cAMP increase. While superfusion of podocytes with bradykinin (100 nM) increased [Ca2+]i, PTHrP(1-36) (100 nM) was without effect on [Ca2+]i. However, PTHrP(1-36) attenuated the bradykinin-induced increase in [Ca2+]i. Our results suggest that PTHrP is an autocrine hormone in podocytes, which selectively activates the cAMP pathway through the PTH/PTHrP receptor.

Animals↗