Ohtomo S, Izuhara Y, Takizawa S, Yamada N, Kakuta T, van Ypersele de Strihou C, Miyata T
Institute of Medical Sciences, Tokai University, Kanagawa, Japan.
Kidney Int. 2007 Dec;72(12):1512-9. doi: 10.1038/sj.ki.5002570. Epub 2007 Sep 26.
Hyperinsulinemia has been implicated in the development of diabetic nephropathy. In the present study we compared the renoprotective effects of the thiazolidinedione, pioglitazone (PGZ), to that of insulin in a hypertensive, obese, type II diabetic rat model. PGZ aggravated obesity and gave less glycemic control than insulin. However, renoprotection was markedly better with PZG compared to insulin as shown by lower proteinuria, improved renal function, and less histological evidence of diabetic glomerular and tubulointerstitial lesions. PZG and insulin both reduced renal accumulation of pentosidine and oxidative stress to a similar extent. In contrast, PGZ but not insulin suppressed enhanced transforming growth factor-beta (TGF-beta) expression. We further confirmed in cultured rat proximal tubular cells that insulin enhanced TGF-beta mRNA expression and protein production. Our results identify hyperinsulinemia and the attendant increase of TGF-beta expression as potential therapeutic targets in diabetes independent of glycemic control. This confirms prior clinical evidence that PZG provides renoprotection in obese, diabetic patients with nephropathy.
高胰岛素血症与糖尿病肾病的发生有关。在本研究中，我们在高血压、肥胖的II型糖尿病大鼠模型中比较了噻唑烷二酮类药物吡格列酮（PGZ）与胰岛素的肾脏保护作用。PGZ加重了肥胖，血糖控制效果不如胰岛素。然而，与胰岛素相比，PZG的肾脏保护作用明显更好，表现为蛋白尿减少、肾功能改善以及糖尿病肾小球和肾小管间质病变的组织学证据减少。PZG和胰岛素在降低戊糖苷肾蓄积和氧化应激方面程度相似。相反，PGZ而非胰岛素抑制了转化生长因子-β（TGF-β）表达的增强。我们在培养的大鼠近端肾小管细胞中进一步证实，胰岛素增强了TGF-β mRNA表达和蛋白质产生。我们的结果表明，高胰岛素血症以及随之而来的TGF-β表达增加是糖尿病中独立于血糖控制的潜在治疗靶点。这证实了先前的临床证据，即PZG为肥胖的糖尿病肾病患者提供肾脏保护作用。
