A protective role of renalase in diabetic nephropathy
A protective role of renalase in diabetic nephropathy
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肾酶在糖尿病肾病中的保护作用
DOI：
10.1042/cs20190995
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发表时间：
2020
期刊：
影响因子：
6
通讯作者：
Wang Feng
中科院分区：
文献类型：
--
作者：
Yin Jianyong;Liu Xuanchen;Zhao Ting;Liang Rulian;Wu Rui;Zhang Fangfei;Kong Yiwei;Liu Limei;Xing Tao;Wang Niansong;Zhao Qing;Wang Feng
肾酶是近年来发现的一种分泌型黄素蛋白，在急性和慢性肾损伤动物模型中具有抗凋亡和抗炎作用。然而，肾酶是否在糖尿病肾病（DN）的发展中发挥类似的作用仍不清楚。本研究验证了肾酶可能在DN的发生中起关键作用并可能具有治疗DN的潜力的假设。肾酶的表达在人DN肾活检组织和db/db小鼠的肾脏中进行了测量。使用基因工程小鼠模型：具有db/db背景的肾酶敲除小鼠，检查肾酶在DN发展中的作用。用肾酶过表达的db/db小鼠评价肾酶对DN的保护作用。此外，还观察了肾酶对高糖诱导的系膜细胞的影响。与健康对照组和db/db小鼠相比，肾酶在人糖尿病肾脏和db/db小鼠肾脏中表达下调，肾酶纯合子敲除可显著增加db/db小鼠的动脉血压，而杂合子敲除则无此作用，肾酶杂合子敲除可导致db/db小鼠白蛋白尿增加和肾小球系膜扩张增加。与野生型同窝小鼠相比，糖尿病肾酶杂合子敲除小鼠的系膜肥大、肾脏炎症和病理损伤显著加重。此外，Renalase过表达显著改善了indb/db小鼠的肾损伤。从机制上讲，肾酶通过抑制细胞外调节蛋白激酶（ERK 1/2）减弱高糖诱导的促纤维化基因表达和p21表达。本研究提示，肾酶对DN的进展具有保护作用，可能成为DN治疗的新靶点。
Renalase, a recently discovered secreted flavoprotein, exerts anti-apoptotic and anti-inflammatory effects against renal injury in acute and chronic animal models. However, whether Renalase elicits similar effects in the development of diabetic nephropathy (DN) remains unclear. The studies presented here tested the hypothesis that Renalase may play a key role in the development of DN and may have therapeutic potential for DN. Renalase expression was measured in human kidney biopsies with DN and in kidneys ofdb/dbmice. The role of Renalase in the development of DN was examined using a genetically engineered mouse model:Renalaseknockout mice withdb/dbbackground. The renoprotective effects of Renalase in DN was evaluated indb/dbmice withRenalaseoverexpression. In addition, the effects of Renalase on high glucose-induced mesangial cells were investigated. Renalase was down-regulated in human diabetic kidneys and in kidneys ofdb/dbmice compared with healthy controls ordb/mmice.Renalasehomozygous knockout increased arterial blood pressure significantly indb/dbmice while heterozygous knockout did not.Renalaseheterozygous knockout resulted in elevated albuminuria and increased renal mesangial expansion indb/dbmice. Mesangial hypertrophy, renal inflammation, and pathological injury in diabeticRenalaseheterozygous knockout mice were significantly exacerbated compared with wild-type littermates. Moreover,Renalaseoverexpression significantly ameliorated renal injury indb/dbmice. Mechanistically, Renalase attenuated high glucose-induced profibrotic gene expression and p21 expression through inhibiting extracellular regulated protein kinases (ERK1/2). The present study suggested that Renalase protected against the progression of DN and might be a novel therapeutic target for the treatment of DN.