Thiazolidinediones Ameliorate Diabetic Nephropathy via Cell Cycle–Dependent Mechanisms

Okada, Tatsuo; Wada, Jun; Hida, Kazuyuki; Eguchi, Jun; Hashimoto, Izumi; Baba, Masako; Yasuhara, Akihiro; Shikata, Kenichi; Makino, Hírofumi

doi:10.2337/db05-1285

Cited by 89 publications

(76 citation statements)

References 43 publications

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“…revealed that gene expressions of podocyte structure-related genes as well as that of oxidative stress and lipid metabolism were restored concomitant with attenuation of albuminuria by PIO treatment (35). Previous study proved that pioglitazone could suppress high glucose-induced phosphorylation of p44/42 mitogen-activated protein kinase and reduce Bcl-2 and p27 (Kip1) protein levels in type 2 diabetes (36). Additionally, thiazolidinediones were found to modulate the glucocorticoid pathway and to exert direct protective effects on podocytes, similar to glucocorticoids (37).…”

Section: Discussionmentioning

confidence: 99%

Hydrochloride pioglitazone protects diabetic rats against podocyte injury through preserving glomerular podocalyxin expression

Xing

Chen

et al. 2014

Arq Bras Endocrinol Metab

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Objective: We sought to test the effect of different dosages of pioglitazone (PIO) on the glomerular expression of podocalyxin and urinary sediment podocalyxin excretion and to explore the potential renoprotective mechanism. Materials and methods: Type 1 diabetes induced with streptozotocin (65 mg/kg) in 36 male Sprague-Dawley rats were randomly allocated to be treated with vehicle or 10, 20, 30 mg/kg/d PIO respectively for 8 weeks. Eight rats were enrolled in the normal control group. Results: At 8 th week, rats were sacrificed for the observation of kidney injury through electron microscope. Glomerular podocalyxin production including mRNA and protein were determined by RT-PCR and immunohistochemistry respectively. Levels of urinary albumin excretion and urinary sediment podocalyxin, kidney injury index were all significantly increased, whereas expression of glomerular podocalyxin protein and mRNA were decreased significantly in diabetic rats compared to normal control. Dosages-dependent analysis revealed that protective effect of PIO ameliorated the physiopathological changes and reached a peak at dosage of 20 mg/kg/d. Conclusion: PIO could alleviate diabetic kidney injury in a dose-dependent pattern and the role may be associated with restraining urinary sediment podocalyxin excretion and preserving the glomerular podocalyxin expression. Arq Bras Endocrinol Metab. 2014;58(6):630-9 Keywords Diabetic nephropathy; podocalyxin; pioglitazone; podocyte; proteinuria RESUMO Objetivo: Buscamos testar os efeitos de diferentes doses de pioglitazona (PIO) sobre a expressão glomerular de podocalixina e sobre a excreção de podocalixina em células do sedimento urinário, além de explorar o potencial mecanismo de proteção renal. Materiais e métodos: O diabetes tipo 1 foi induzido em 36 ratos Sprague-Dawley machos com estreptozotocina (65 mg/kg). Os animais foram tratados apenas com o veículo, ou com 10, 20, 30 mg/kg/d de PIO por 8 semanas. Oito ratos foram colocados no grupo controle. Resultados: Na oitava semana, os ratos foram sacrificados para se observar a lesão renal em microscopia eletrônica. A produção de podocalixina glomerular, incluindo mRNA e proteína, foi determinada por RT-PCR e imuno-histoquímica, respectivamente. Os níveis urinários de albumina e podocalixina nas células do sedimento urinário e o índice de lesão renal estavam todos significativamente aumentados, enquanto a expressão glomerular da proteína podocalixina e do mRNA estava significativamente diminuída em ratos diabéticos comparados com o controle normal. A análise dos efeitos dose-dependentes revelou que o efeito protetor da PIO melhorou as mudanças fisiopatológicas e atingiu um pico na dose de 20 mg/kg/ dia. Conclusão: A PIO pode melhorar a injúria renal de forma dose-dependente e este papel pode estar associado com a prevenção da excreção de podocalixina nas células do sedimento urinário e com a preservação da expressão glomerular de podocalixina. Arq Bras Endocrinol Metab. 2014;58(6):630-9

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Section: Discussionmentioning

confidence: 99%

Hydrochloride pioglitazone protects diabetic rats against podocyte injury through preserving glomerular podocalyxin expression

Xing

Chen

et al. 2014

Arq Bras Endocrinol Metab

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“…Both PPAR␣ and -␥ agonists have been shown to be potentially therapeutic agents in treating diabetic nephropathy (7)(8)(9)(10). However, little is known about the efficacy of PPAR␣ and -␥ dual activators on renal complications in type 2 diabetes.…”

Section: Discussionmentioning

confidence: 99%

Peroxisome Proliferator–Activated Receptor α/γ Dual Agonist Tesaglitazar Attenuates Diabetic Nephropathy in db/db Mice

Ryong

Zhang

et al. 2007

Diabetes

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Peroxisome proliferator-activated receptors (PPARs) are nuclear transcription factors and play a central role in insulin sensitivity, lipid metabolism, and inflammation. Both PPAR␣ and -␥ are expressed in the kidney, and their agonists exhibit renoprotective effects in type 2 diabetes. In the present studies, we investigated the effect of the PPAR␣/␥ dual agonist tesaglitazar on diabetic nephropathy in type 2 diabetic db/db mice. Treatment of db/db mice with tesaglitazar for 3 months significantly lowered fasting plasma glucose and homeostasis model assessment of insulin resistance levels but had little effect on body weight, adiposity, or cardiac function. Treatment with tesaglitazar was associated with reduced plasma insulin and total triglyceride levels and increased plasma adiponectin levels. Notably, tesaglitazar markedly attenuated albuminuria and significantly lowered glomerulofibrosis, collagen deposition, and transforming growth factor-␤1 expression in renal tissues of db/db mice. In cultured mesangial cells and proximal tubule cells, where both PPAR␣ and -␥ were expressed, tesaglitazar treatment abolished high glucoseinduced total collagen protein production and type I and IV collagen gene expression. Collectively, tesaglitazar treatment not only improved insulin resistance, glycemic control, and lipid profile but also markedly attenuated albuminuria and renal glomerular fibrosis in db/db mice. These findings support the utility of dual PPAR␣/␥ agonists in treating type 2 diabetes and diabetic nephropathy.

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“…MES13 cells, glomerular mesangial cells from an SV40 transgenic mouse, were grown as previously described [22]. mProx24 cells, a murine renal proximal tubular epithelial cell line derived from the kidney of an adult C57BL/6J mouse [23], were cultured in Dulbecco’s modified Eagle’s medium (Sigma-Aldrich, St. Louis, Mo., USA) supplemented with 5.5 m M D -glucose, 10% fetal bovine serum, 100 U/ml penicillin, and 100 mg/ml streptomycin at 37°C in 5% CO 2 .…”

Section: Methodsmentioning

confidence: 99%

Telmisartan Attenuates Diabetic Nephropathy by Suppressing Oxidative Stress in <b><i>db/db</i></b> Mice

Sato-Horiguchi¹,

Ogawa²,

Wada³

et al. 2013

Nephron Exp Nephrol

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Background/Aims: Telmisartan, an angiotensin II type 1 receptor blocker, is widely used to treat hypertension and kidney diseases, including diabetic nephropathy, because of its renoprotective effects. However, the mechanism by which telmisartan prevents proteinuria and renal dysfunction in diabetic nephropathy is still unclear. In this study, we examined the effects of telmisartan against diabetic nephropathy in db/db mice. Methods: Telmisartan was administered at a dose of 5 mg/kg/day for 3 weeks to db/db (diabetic) and db/m (control) mice. Urinary albumin excretion, renal histology, and the gene expression of oxidative stress and inflammatory markers in renal tissue were determined. To evaluate the effects of telmisartan on reactive oxygen species (ROS) production, superoxide was detected by dihydroethidium (DHE) staining in vivo and in vitro. Results: Telmisartan reduced albuminuria, mesangial matrix expansion, macrophage infiltration, and the expression of ROS markers (NADPH oxidase 4- and 8-hydroxydeoxyguanosine) and inflammatory cytokines (monocyte chemoattractant protein-1, osteopontin, and transforming growth factor-β) in the kidney. DHE staining showed that telmisartan decreased ROS generation in the kidney and in cultured mesangial and proximal tubular epithelial cells. Conclusions: Taken together, these findings indicate that telmisartan protects against diabetic nephropathy by reducing diabetes-induced oxidative stress.

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Thiazolidinediones Ameliorate Diabetic Nephropathy via Cell Cycle–Dependent Mechanisms

Cited by 89 publications

References 43 publications

Hydrochloride pioglitazone protects diabetic rats against podocyte injury through preserving glomerular podocalyxin expression

Hydrochloride pioglitazone protects diabetic rats against podocyte injury through preserving glomerular podocalyxin expression

Peroxisome Proliferator–Activated Receptor α/γ Dual Agonist Tesaglitazar Attenuates Diabetic Nephropathy in db/db Mice

Telmisartan Attenuates Diabetic Nephropathy by Suppressing Oxidative Stress in <b><i>db/db</i></b> Mice

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