Peroxisome Proliferator-Activated Receptor-γ Agonist Rosiglitazone Prevents Albuminuria but Not Glomerulosclerosis in Experimental Diabetes

Setti, G; Hayward, A; Dessapt, Cecile; Barone, Francesca; Buckingham, Robin E.; White, Kathryn; Bilous, Rudolf W.; Kawachi, Hiroshi; Gruden, Gabriella; Viberti, Giancarlo; Gnudi, Luigi

doi:10.1159/000320129

Cited by 16 publications

(13 citation statements)

References 56 publications

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“…The present results were consistent with other experimental studies that demonstrated that TZDs are beneficial for renal and cardiovascular protection (13,18,22,23). ROG intervention attenuated hyperuricemia, which is generally acknowledged as an independent risk factor of CKD.…”

Section: Discussionsupporting

confidence: 93%

“…Furthermore, this is the first study to demonstrate that ROG was able to attenuate renal damage and metabolic disorders in adenine-induced CKD models. ROG, a PPAR-γ agonist, has been indicated to exert cardiovascular and renal protection through the improvement of anti-inflammation, antiproliferation and antioxidative stress (13)(14)(15)(16)(17)(18). These data demonstrated that ROG exerts a polyphenic profit on the cardiovascular and renal system.…”

Section: Discussionmentioning

confidence: 93%

“…TZDs are used to treat diabetes mellitus, and are known to exert their glucose-lowering effects by reducing insulin resistance through the stimulation of PPAR-γ nuclear receptor. In addition to improving glycemic control, TZDs have been demonstrated to exert beneficial effects on renal and vascular protection (11)(12)(13)(14)(15). In the present study, the effect of rosiglitazone (ROG) on proteinuria and renal function in CKD models induced by adenine was analyzed, and the contribution of the Pi-PTH-FGF-23 system was investigated.…”

Section: Introductionmentioning

confidence: 97%

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Rosiglitazone alleviates injury in rats with adenine-induced chronic kidney disease

Huang

Yan

Zheng

et al. 2013

Molecular Medicine Reports

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Abstract. Rosiglitazone (ROG) has been shown to exert beneficial effects on glycemic control and renal protection. Circulatory fibroblast growth factor-23 (FGF-23) is a novel independent risk factor for chronic kidney disease (CKD) progression. The current study focused on how ROG impacts on injury of the kidney, and whether FGF-23 is involved in the process. A total of 24 male Sprague Dawley rats, weighing 250-280 g, were divided into four groups (n=6 per group): i) Normal; ii) ROG controls, treated with ROG (10 mg/kg/day); iii) CKD models, treated with adenine (200 mg/kg/day); and iv) ROG treatment, treated with ROG (10 mg/kg/day) and adenine (200 mg/kg/day). The rats were sacrificed after four weeks, and serum, urine and kidney tissues were collected. The data revealed that the serum levels of inorganic phosphate (Pi), intact parathyroid hormone (iPTH) and FGF-23 were significantly higher in the CKD models compared with those in the normal group (P<0.01), while ROG significantly reduced the serum levels of Pi, iPTH and FGF-23 (P<0.01). The ratio of protein/creatine (Cr) in the urine and the serum levels of Cr, blood urea nitrogen and uric acid were significantly increased in the CKD models compared with the normal group (P<0.01), however, ROG significantly reduced these parameters (P<0.05). Furthermore, ROG significantly alleviated the tubule interstitial damage index of the CKD models in comparison with that of the controls. These results indicated that ROG mitigates the lesions of chronic kidney disease induced by adenine, and that the system of Pi-PTH-FGF-23 may contribute to this process. The possible mechanisms underlying this process require confirmation in future studies.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 97%

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Rosiglitazone alleviates injury in rats with adenine-induced chronic kidney disease

Huang

Yan

Zheng

et al. 2013

Molecular Medicine Reports

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“…In rats with STZ-induced diabetes, rosiglitazone has no effects on hyperglycemia, glomerulosclerosis, or basement membrane thickening, but reduces albuminuria and renal macrophage infiltration (Setti et al 2010). Thus, the anti-inflammatory effects of rosiglitazone may contribute to the marked renal protection in the current study.…”

Section: Discussionmentioning

confidence: 59%

Diabetic nephropathy and long-term treatment effects of rosiglitazone and enalapril in obese ZSF1 rats

Bilan¹,

Salah²,

Bastacky³

et al. 2011

Journal of Endocrinology

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Diabetic nephropathy (DN) is a major cause of end-stage renal disease. Yet the pathogenic mechanisms underlying the development of DN are not fully defined, partially due to lack of suitable models that mimic the complex pathogenesis of renal disease in diabetic patients. In this study, we describe early and late renal manifestations of DN and renal responses to long-term treatments with rosiglitazone or high-dose enalapril in ZSF1 rats, a model of metabolic syndrome, diabetes, and chronic renal disease. At 8 weeks of age, obese ZSF1 rats developed metabolic syndrome and diabetes (hyperglycemia, glucosuria, hyperlipidemia, and hypertension) and early signs of renal disease (proteinuria, glomerular collagen IV deposition, tubulointerstitial inflammation, and renal hypertrophy). By 32 weeks of age, animals developed renal histopathology consistent with DN, including mesangial expansion, glomerulosclerosis, tubulointerstitial inflammation and fibrosis, tubular dilation and atrophy, and arteriolar thickening. Rosiglitazone markedly increased body weight but reduced food intake, improved glucose control, and attenuated hyperlipidemia and liver and kidney injury. In contrast, rosiglitazone markedly increased cardiac hypertrophy via a blood pressure-independent mechanism. High-dose enalapril did not improve glucose homeostasis, but normalized blood pressure, and nearly prevented diabetic renal injury. The ZSF1 model thus detects the clinical observations seen with rosiglitazone and enalapril in terms of primary and secondary endpoints of cardiac and renal effects. This and previous reports indicate that the obese ZSF1 rat meets currently accepted criteria for progressive experimental diabetic renal disease in rodents, suggesting that this may be the best available rat model for simulation of human DN.

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“…They are widely used for diabetes therapy as insulinsensitizing agents. Recent studies have demonstrated that TZDs could reduce albuminuria in patients with type 2 diabetics and diabetic animals (11,12). The protective effect may be partly related to its effect in alleviating podocyte injury.…”

mentioning

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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Peroxisome Proliferator-Activated Receptor-γ Agonist Rosiglitazone Prevents Albuminuria but Not Glomerulosclerosis in Experimental Diabetes

Cited by 16 publications

References 56 publications

Rosiglitazone alleviates injury in rats with adenine-induced chronic kidney disease

Rosiglitazone alleviates injury in rats with adenine-induced chronic kidney disease

Diabetic nephropathy and long-term treatment effects of rosiglitazone and enalapril in obese ZSF1 rats

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

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