Suppressors of Cytokine Signaling Abrogate Diabetic Nephropathy
Suppressors of Cytokine Signaling Abrogate Diabetic Nephropathy
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DOI：
10.1681/asn.2009060625
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发表时间：
2010-05-01
影响因子：
13.6
通讯作者：
Gomez-Guerrero, Carmen
中科院分区：
文献类型：
--
作者：
Ortiz-Munoz, Guadalupe;Lopez-Parra, Virginia;Gomez-Guerrero, Carmen
Janus激酶/信号转导和转录激活因子（JAK/STAT）的激活是高血糖导致肾损伤的重要机制，表明调节该途径可能预防糖尿病的肾脏和血管并发症。在这里，我们研究了细胞因子信号抑制因子（SOCS）作为JAK/STAT激活的细胞内负调节因子在糖尿病肾病中的作用。在大鼠模型中，诱导糖尿病导致JAK/STAT激活，SOCS1和SOCS3表达增加。在人类糖尿病肾病患者的活组织检查中，我们观察到肾小球和小管间质SOCS蛋白的表达增加。在体外，高浓度葡萄糖激活了人系膜和小管细胞中的JAK/STAT/SOCS。SOCS的过表达逆转了葡萄糖诱导的JAK/STAT通路的激活、STAT依赖基因（趋化因子、生长因子和细胞外基质蛋白）的表达和细胞增殖。在体内，向糖尿病大鼠肾内递送表达SOCS1和SOCS3的腺病毒可显著改善肾功能，减少与糖尿病相关的肾脏病变，如肾小球系膜扩张、纤维化和巨噬细胞内流。SOCS基因传递也降低了糖尿病肾脏中STAT1和STAT3的激活以及促炎和促纤维化蛋白的表达。总之，这些结果为JAK/STAT/SOCS轴与肾脏高血糖诱导的细胞反应之间的联系提供了直接证据。通过增加细胞内SOCS蛋白抑制JAK/STAT通路可能具有治疗糖尿病肾病的潜力。
Activation of Janus kinase/signal transducers and activators of transcription (JAK/STAT) is an important mechanism by which hyperglycemia contributes to renal damage, suggesting that modulation of this pathway may prevent renal and vascular complications of diabetes. Here, we investigated the involvement of suppressors of cytokine signaling (SOCS) as intracellular negative regulators of JAK/STAT activation in diabetic nephropathy. In a rat model, inducing diabetes resulted in JAK/STAT activation and increased expression of SOCS1 and SOCS3. In humans, we observed increased expression of glomerular and tubulointerstitial SOCS proteins in biopsies of patients with diabetic nephropathy. In vitro, high concentrations of glucose activated JAK/STAT/SOCS in human mesangial and tubular cells. Overexpression of SOCS reversed the glucose-induced activation of the JAK/STAT pathway, expression of STAT-dependent genes (chemokines, growth factors, and extracellular matrix proteins), and cell proliferation. In vivo, intrarenal delivery of adenovirus expressing SOCS1 and SOCS3 to diabetic rats significantly improved renal function and reduced renal lesions associated with diabetes, such as mesangial expansion, fibrosis, and influx of macrophages. SOCS gene delivery also decreased the activation of STAT1 and STAT3 and the expression of proinflammatory and profibrotic proteins in the diabetic kidney. In summary, these results provide direct evidence for a link between the JAK/STAT/SOCS axis and hyperglycemia-induced cell responses in the kidney. Suppression of the JAK/STAT pathway by increasing intracellular SOCS proteins may have therapeutic potential in diabetic nephropathy.