PTPN2 improved renal injury and fibrosis by suppressing STAT-induced inflammation in early diabetic nephropathy
PTPN2 improved renal injury and fibrosis by suppressing STAT-induced inflammation in early diabetic nephropathy
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PTPN2 通过抑制早期糖尿病肾病 STAT 诱导的炎症来改善肾损伤和纤维化
DOI：
10.1111/jcmm.14304
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发表时间：
2019-06-01
影响因子：
5.3
通讯作者：
Zhong, Ming
中科院分区：
文献类型：
--
作者：
Li, Ya;Zhou, Huimin;Zhong, Ming
糖尿病肾病（diabetic nephropathy，DN）是一种由代谢紊乱引起的慢性炎症性疾病。近年来的研究表明，蛋白酪氨酸磷酸酶非受体2（PTPN 2）可以改善代谢紊乱和抑制炎症反应。本研究探讨PTPN 2在DN中的作用及其可能的细胞机制。在合并高胆固醇血症和高胆固醇血症的小鼠模型（链脲佐菌素糖尿病，ApoE（-/-）小鼠）中，小鼠表现出严重的胰岛素抵抗、肾功能障碍、微炎症、随后的细胞外基质扩张和PTPN 2表达降低。我们发现用PTPN 2处理的小鼠显示出降低的血清肌酐、血清BUN和蛋白尿。PTPN 2基因治疗显著减轻代谢紊乱和高血压。此外，PTPN 2基因转移显著抑制了DN中信号转导和转录激活因子（STAT）的肾脏激活、STAT依赖性促炎和促纤维化基因表达以及淋巴细胞内流，表明PTPN 2通过抑制STAT信号通路的激活而在体内发挥抗炎作用。PTPN 2过表达抑制高糖诱导的STAT磷酸化、靶基因表达和小鼠系膜和肾小管上皮细胞增殖，提示PTPN 2对STAT激活的作用不依赖于血糖变化。我们的研究结果表明，PTPN 2基因治疗可以通过改善代谢紊乱和抑制肾脏STAT依赖性微炎症来对DN发挥保护作用，这表明其在治疗人类DN方面具有潜在作用。
Diabetic nephropathy (DN) is a chronic inflammatory disease triggered by disordered metabolism. Recent studies suggested that protein tyrosine phosphatase non-receptor type 2 (PTPN2) could ameliorate metabolic disorders and suppress inflammatory responses. This study investigated PTPN2's role in modulating DN and the possible cellular mechanisms involved. In a mouse model combining hyperglycaemia and hypercholesterolaemia (streptozotocin diabetic, ApoE(-/-) mice), mice showed severe insulin resistance, renal dysfunction, micro-inflammation, subsequent extracellular matrix expansion and decreased expression of PTPN2. We found that mice treated with PTPN2 displayed reduced serum creatinine, serum BUN and proteinuria. PTPN2 gene therapy markedly attenuated metabolic disorders and hyperglycaemia. In addition, PTPN2 gene transfer significantly suppressed renal activation of signal transducers and activators of transcription (STAT), STAT-dependent pro-inflammatory and pro-fibrotic genes expression, and influx of lymphocytes in DN, indicating anti-inflammatory effects of PTPN2 by inhibiting the activation of STAT signalling pathway in vivo. Furthermore, PTPN2 overexpression inhibited the high-glucose induced phosphorylation of STAT, target genes expression and proliferation in mouse mesangial and tubuloepithelial cells, suggesting that the roles of PTPN2 on STAT activation was independent of glycaemic changes. Our results demonstrated that PTPN2 gene therapy could exert protective effects on DN via ameliorating metabolic disorders and inhibiting renal STAT-dependent micro-inflammation, suggesting its potential role for treatment of human DN.