The Podocyte: a Potential Therapeutic Target in Diabetic Nephropathy?

Marshall, Sally M.

doi:10.2174/138161207781662957

Cited by 37 publications

(37 citation statements)

References 55 publications

(71 reference statements)

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“…Podocytes, as highly differentiated terminal cells, combine with slit diaphragms among foot processes to form the outermost layer of the glomerular filtration barrier. The fusion and disappearance of foot processes is one of the initial mechanisms of proteinuria formation [8,9], while urinary protein excretion can aggravate podocyte injury. In this study, HQH reduced proteinuria in ADR rats, simultaneously, significantly alleviated podocyte injury, indicating that proteinuria is closely related to podocyte injury.…”

Section: Discussionmentioning

confidence: 99%

Protective effects of Huang Qi Huai granules on adriamycin nephrosis in rats

et al. 2011

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Huang Qi Huai (HQH) granules, a mixture of Chinese herbs, contains trametes robiniophila murr, wolfberry fruit, and Polygonatum. We investigated the mechanism of the protective effects of HQH on adriamycin nephrosis (ADR) in rats. Adriamycin nephrotic rats were induced by a single dose of 5 mg/kg adriamycin. For the HQH-treated adriamycin nephrosis group, 1 day after treatment with 5 mg/kg adriamycin, the rats were administered once-daily oral gavage of 2 mg/kg HQH for 15 days. All the rats were killed at day 15. Histological changes were observed by light microscopy and transmission electron microscope. Nephrin and podocin expression levels were measured by real-time RT-PCR and Western blot. Proteinuria was measured by the Bradford protein assay. Serum TNF-α and IL-1β levels were evaluated by ELISA. Macrophage infiltration was detected by immunohistochemistry and immunoblotting, respectively. ADR rats showed heavy proteinuria, podocyte and tubulointerstitial injury, macrophage infiltration, and increased levels of serum cytokines TNF-α and IL-1β. HQH significantly ameliorated the adriamycin-induced renal injury. These data were validated in the cultured podocytes. The podocytes were treated by adriamycin in the presence or absence of HQH and nephrin and podocin expression and TNF-α and IL-1β synthesis and secretion were determined by real-time RT-PCR, immunoblotting, and ELISA, respectively. Adriamycin significantly reduced nephrin and podocin expression, which was significantly restored by the treatment of HQH. HQH treatment inhibited adriamycin-induced TNF-α and IL-1β expression. Our findings suggest that HQH significantly reduces proteinuria, prevents podocyte injury, and ameliorates tubulointerstitial damage. Inhibition of inflammatory cytokine expression and macrophage infiltration may be the protective mechanism of HQH.

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Section: Discussionmentioning

confidence: 99%

Protective effects of Huang Qi Huai granules on adriamycin nephrosis in rats

et al. 2011

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“…24 Podocyte ROI production is stimulated by hyperglycemia, and signs of podocyte activation such as increased vascular endothelial growth factor production are ameliorated by antioxidants. 25 In diabetes, there are also angiotensin II-mediated increases in podocyte NADPH oxidase activity.…”

Section: Discussionmentioning

confidence: 99%

Inducible Nitric Oxide Synthase Inhibitor SD-3651 Reduces Proteinuria in MRL/lpr Mice Deficient in the NOS2 Gene

Njoku

Self

Ruiz

et al. 2008

Journal of Investigative Medicine

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Several studies have demonstrated the effectiveness of arginine analog nitric oxide synthase (NOS) inhibitor therapy in preventing and treating murine lupus nephritis. However, MRL/MpJ-FASlpr (MRL/lpr) mice lacking a functional NOS2 (inducible NOS [iNOS]) gene (NOS2−/−) develop proliferative glomerulonephritis in a fashion similar to their wild-type (wt) littermates. This finding suggests that the effect of arginine analog NOS inhibitors is through a non-iNOS–mediated mechanism. This study was designed to address this hypothesis. NOS2−/− mice were given either vehicle or a NOS inhibitor (SD-3651) to determine if pharmacological NOS inhibition prevented glomerulonephritis, using wt mice as positive controls. Urine was collected fortnightly to measure albumin. At the time of full disease expression in wt mice, all mice were killed, and renal tissue was examined for light, immunofluorescence, and electron microscopic evidence of disease. Serum was analyzed for anti–double-stranded DNA antibody production. NOS2−/− mice had higher serum anti–double-stranded DNA antibody antibody levels than those of wt mice. SD-3651 therapy reduced proteinuria, glomerular immunoglobulin G deposition, and electron microscopic evidence of podocytopathy and endothelial cell swelling without affecting proliferative lesions by light microscopy. These studies confirm that genetic iNOS deficiency alone is insufficient to prevent proliferative glomerulonephritis and suggest that iNOS activity may inhibit autoantibody production. These results also suggest that SD-3651 therapy acts via a non–iNOS-mediated mechanism to prevent endothelial cell and podocyte pathology. Studies that elucidate this mechanism could provide a useful drug target for the treatment of nephritis.

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“…2 Altered podocyte function occurs early in the development of diabetic nephropathy and can affect cell-cell interactions, attachment to the glomerular basement membrane, and apoptosis. [2][3][4][5][6][7][8][9][10] In humans, COX-2 expression is readily detectable in glomerular podocytes of adults, 11,12 and expression levels have been reported to increase during acute renal allograft rejection. 13,14 Occasional COX-2-positive podocytes are also detectable in adult rats, 15,16 and we have previously reported that in rat models of diabetes there is increased COX-2 expression in podocytes, and also in mesangial cells and macula densa cells, and have shown that COX-2 inhibition can attenuate proteinuria and retard diabetic nephropathy progression.…”

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confidence: 99%

Podocyte COX-2 Exacerbates Diabetic Nephropathy by Increasing Podocyte (Pro)renin Receptor Expression

Cheng¹,

Fan²,

Moeckel³

et al. 2011

Journal of the American Society of Nephrology

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Diabetic nephropathy (DN) increases podocyte cyclooxygenase-2 (COX-2) expression, and COX-2 inhibition reduces proteinuria and glomerular injury in animal models of diabetes. To investigate the role of podocyte COX-2 in development of diabetic nephropathy, we employed a streptozotocin model of diabetic mellitus in wild-type and transgenic mice expressing COX-2 selectively in podocytes. Progressive albuminuria developed only in diabetic COX-2 transgenic mice despite hyperglycemia, BP, and GFR being similar to those in wild-type mice. Transgenic mice also manifested significant foot-process effacement, moderate mesangial expansion, and segmental thickening of the glomerular basement membrane. In cultured podocytes overexpressing COX-2, high glucose induced cell injury and increased both expression of the pro(renin) receptor and activation of the renin-angiotensin system. Downregulation of the (pro)renin receptor attenuated the injury induced by high glucose. In vivo, podocyte pro(renin) receptor expression increased in diabetic COX-2-transgenic mice, and treatment with a COX-2 inhibitor abrogated the upregulation of (pro)renin receptor and reduced albuminuria, footprocess effacement, and mesangial matrix expansion. In summary, these results demonstrate that increased expression of podocyte COX-2 predisposes to diabetic glomerular injury and that the (pro)-renin receptor may be one mediator for this increased susceptibility to injury. Hyperglycemia-mediated metabolic abnormalities, hemodynamic abnormalities, and oxidative stress have all been implicated in the pathogenesis of diabetic nephropathy. 1 Diabetes can affect numerous cell types in the kidney, including glomerular podocytes, mesangial and endothelial cells, tubular epithelia, interstitial fibroblasts, and vascular endothelia. 2 Altered podocyte function occurs early in the development of diabetic nephropathy and can affect cell-cell interactions, attachment to the glomerular basement membrane, and apoptosis. [2][3][4][5][6][7][8][9][10] In humans, COX-2 expression is readily detectable in glomerular podocytes of adults, 11,12 and expression levels have been reported to increase during acute renal allograft rejection. 13,14 Occasional COX-2-positive podocytes are also detectable in adult rats, 15,16 and we have previously reported that in rat models of diabetes there is increased COX-2 expression in podocytes, and also in mesangial cells and macula densa cells, and have shown that COX-2 inhibition can attenuate proteinuria and retard diabetic nephropathy progression. 15 In this study, we investigated the role of increased COX-2 in diabetes-induced podocyte injury. Our results indicate that increased podocyte expression of COX-2 increases susceptibility

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The Podocyte: a Potential Therapeutic Target in Diabetic Nephropathy?

Cited by 37 publications

References 55 publications

Protective effects of Huang Qi Huai granules on adriamycin nephrosis in rats

Protective effects of Huang Qi Huai granules on adriamycin nephrosis in rats

Inducible Nitric Oxide Synthase Inhibitor SD-3651 Reduces Proteinuria in MRL/lpr Mice Deficient in the NOS2 Gene

Podocyte COX-2 Exacerbates Diabetic Nephropathy by Increasing Podocyte (Pro)renin Receptor Expression

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