Isshiki Keiji, He Zhiheng, Maeno Yasuhiro, Ma Ronald C, Yasuda Yutaka, Kuroki Tatsuya, White Gregory S, Patti Mary E, Weir Gordon C, King George L
Research Division, Joslin Diabetes Center, One Joslin Place, Harvard Medical School, Boston, Massachusetts 02215, USA.
Kidney Int. 2008 Dec;74(11):1434-43. doi: 10.1038/ki.2008.403. Epub 2008 Aug 13.
Renal hypertrophy and deposition of extracellular matrix proteins are consistent findings in diabetic nephropathy and these processes can be halted or reversed by euglycemic control. Using DNA microarray analysis of glomerular RNA from control and diabetic rats we found that the expression levels of insulin-like growth factor 1 receptor (IGF-1R) were increased while those of suppressor of cytokine signaling 2 (SOCS2) and STAT5 were decreased. All of these changes were normalized by islet cell transplantation. Overexpression of SOCS2 in rat mesangial cells inhibited IGF-1-induced activation of extracellular signal-regulated kinase, which subsequently reduced type IV collagen and DNA synthesis, an effect due to interaction of SOCS2 with IGF-1R. Inhibition of SOCS2 overexpression by small interfering RNA suppressed IGF-1R-mediated actions by preventing phosphorylation of tyrosine 317 in the p66Shc adaptor protein; however, overexpression of either SOCS1 or SOCS3 did not affect IGF-1R signaling. Insulin directly increased STAT5 and SOCS2 expression in mesangial cells. This study shows that insulin can inhibit the mitogenic action of IGF-1 in mesangial cells by regulating STAT5/SOCS2 expression. Insulin deficiency may contribute to the mesangial expansion found in diabetes through reduced STAT5/SOCS2 expression.
肾肥大和细胞外基质蛋白沉积是糖尿病肾病的常见表现，通过血糖正常化控制可以阻止或逆转这些过程。利用DNA微阵列分析对照大鼠和糖尿病大鼠肾小球RNA，我们发现胰岛素样生长因子1受体（IGF-1R）的表达水平升高，而细胞因子信号转导抑制因子2（SOCS2）和信号转导和转录激活因子5（STAT5）的表达水平降低。所有这些变化都通过胰岛细胞移植恢复正常。在大鼠系膜细胞中过表达SOCS2可抑制IGF-1诱导的细胞外信号调节激酶激活，随后减少IV型胶原和DNA合成，这是由于SOCS2与IGF-1R相互作用所致。通过小干扰RNA抑制SOCS2过表达可通过阻止p66Shc衔接蛋白中酪氨酸317的磷酸化来抑制IGF-1R介导的作用；然而，过表达SOCS1或SOCS3并不影响IGF-1R信号传导。胰岛素可直接增加系膜细胞中STAT5和SOCS2的表达。本研究表明，胰岛素可通过调节STAT5/SOCS2表达来抑制系膜细胞中IGF-1的促有丝分裂作用。胰岛素缺乏可能通过降低STAT5/SOCS2表达导致糖尿病中发现的系膜扩张。
