Yang Suxia, Zhang Junwei, Wang Shiying, Zhao Xinxin, Shi Jun
Department of Nephrology, Huaihe Hospital of Henan University, Kaifeng, 475000, China.
Oncotarget. 2017 Aug 24;8(53):91185-91198. doi: 10.18632/oncotarget.20434. eCollection 2017 Oct 31.
Suppressor of cytokine signaling 2 (SOCS2) was reported to be involved in the development of Diabetic Nephropathy (DN). However, its underlying mechanism remains undefined. Western blot was carried out to determine the expressions of SOCS2, Toll-like receptors 4 (TLR4) and nuclear factor kappa B (NF-κB) pathway-related proteins in DN patients, streptozotocin (STZ)-induced DN rats and high glucose (HG)-stimulated podocytes. The effects of SOCS2 overexpression on renal injury, the inflammatory cytokines production, renal pathological changes, apoptosis and the TLR4/NF-κB pathway in DN rats or HG-stimulated podocytes were investigated. TLR4 antagonist TAK-242 and NF-κB inhibitor PDTC were used to confirm the functional mechanism of SOCS2 overexpression in HG-stimulated podocytes. SOCS2 was down-regulated, while TLR4 and NF-κB were up-regulated in renal tissues of DN patients and DN rats. Ad-SOCS2 infection alleviated STZ-induced renal injury and pathological changes and inhibited STZ-induced IL-6, IL-1β and MCP-1 generation and activation of the TLR4/NF-κB pathway in DN rats. SOCS2 overexpression attenuated apoptosis, suppressed the inflammatory cytokines expression, and inactivated the TLR4/NF-κB pathway in HG-stimulated podocytes. Suppression of the TLR4/NF-κB pathway enhanced the inhibitory effect of SOCS2 overexpression on apoptosis and inflammatory cytokines expressions in HG-stimulated podocytes. SOCS2 overexpression alleviated the development of DN by inhibiting the TLR4/NF-κB pathway, contributing to developing new therapeutic strategies against DN.
细胞因子信号转导抑制因子2（SOCS2）据报道参与糖尿病肾病（DN）的发展。然而，其潜在机制仍不明确。进行蛋白质免疫印迹法以测定DN患者、链脲佐菌素（STZ）诱导的DN大鼠和高糖（HG）刺激的足细胞中SOCS2、Toll样受体4（TLR4）和核因子κB（NF-κB）通路相关蛋白的表达。研究了SOCS2过表达对DN大鼠或HG刺激的足细胞肾损伤、炎性细胞因子产生、肾脏病理变化、细胞凋亡以及TLR4/NF-κB通路的影响。使用TLR4拮抗剂TAK-242和NF-κB抑制剂PDTC来证实SOCS2过表达在HG刺激的足细胞中的功能机制。在DN患者和DN大鼠的肾组织中，SOCS2表达下调，而TLR4和NF-κB表达上调。腺病毒载体介导的SOCS2感染减轻了STZ诱导的肾损伤和病理变化，并抑制了STZ诱导的DN大鼠中IL-6、IL-1β和MCP-1的产生以及TLR4/NF-κB通路的激活。SOCS2过表达减轻了HG刺激的足细胞的细胞凋亡，抑制了炎性细胞因子的表达，并使TLR4/NF-κB通路失活。抑制TLR4/NF-κB通路增强了SOCS2过表达对HG刺激的足细胞凋亡和炎性细胞因子表达的抑制作用。SOCS2过表达通过抑制TLR4/NF-κB通路减轻了DN的发展，有助于开发针对DN的新治疗策略。
