Up-regulation of Nrf2 is involved in FGF21-mediated fenofibrate protection against type 1 diabetic nephropathy.
Up-regulation of Nrf2 is involved in FGF21-mediated fenofibrate protection against type 1 diabetic nephropathy.
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Nrf2 的上调参与 FGF21 介导的非诺贝特对 1 型糖尿病肾病的保护作用。
DOI：
10.1016/j.freeradbiomed.2016.02.002
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发表时间：
2016-04
影响因子：
7.4
通讯作者：
Cai L
中科院分区：
文献类型：
--
作者：
Cheng Y;Zhang J;Guo W;Li F;Sun W;Chen J;Zhang C;Lu X;Tan Y;Feng W;Fu Y;Liu GC;Xu Z;Cai L
降脂药物非诺贝特（FF）是一种过氧化物酶体增殖物激活受体α（PPARα）激动剂，对2型糖尿病肾病（DN）具有有益作用。我们研究了FF是否可以预防1型DN的发展，以及潜在的机制。在C57 BL/6 J小鼠中通过单次腹腔注射链脲佐菌素诱导糖尿病。小鼠每隔一天经口灌胃FF 100 mg/kg，持续3个月和6个月。糖尿病诱导的肾脏氧化应激、炎症、细胞凋亡、脂质和胶原蓄积以及肾功能不全伴随着PI 3 K、Akt和GSK-3β磷酸化的显著降低以及Fyn [核因子（红细胞衍生2）样2（Nrf 2）的负调节因子]核蓄积的增加。所有这些不良反应均被FF治疗显著减弱。FF还显著增加糖尿病和非糖尿病肾脏中成纤维细胞生长因子21（FGF 21）的表达，并增强Nrf 2功能。此外，FF诱导的糖尿病肾损伤的改善，包括PI 3 K/Akt/GSK-3β/Fyn通路的刺激和Nrf 2功能的增强在FGF 21敲除小鼠中被消除，证实了FGF 21在FF诱导的肾保护中的关键作用。这些结果首次表明，FF通过上调FGF 21和刺激PI 3 K/Akt/GSK-3β/Fyn介导的Nrf 2通路活化来预防DN的发展。
The lipid lowering medication, fenofibrate (FF), is a peroxisome proliferator-activated receptor-alpha (PPARα) agonist, possessing beneficial effects for type 2 diabetic nephropathy (DN). We investigated whether FF can prevent the development of type 1 DN, and the underlying mechanisms. Diabetes was induced by a single intraperitoneal injection of streptozotocin in C57BL/6J mice. Mice were treated with oral gavage of FF at 100 mg/kg every other day for 3 and 6 months. Diabetes-induced renal oxidative stress, inflammation, apoptosis, lipid and collagen accumulation, and renal dysfunction were accompanied by significant decrease in PI3K, Akt, and GSK-3β phosphorylation as well as an increase in the nuclear accumulation of Fyn [a negative regulator of nuclear factor (erythroid-derived 2)-like 2 (Nrf2)]. All these adverse effects were significantly attenuated by FF treatment. FF also significantly increased fibroblast growth factor 21 (FGF21) expression and enhanced Nrf2 function in diabetic and non-diabetic kidneys. Moreover, FF-induced amelioration of diabetic renal damage, including the stimulation of PI3K/Akt/GSK-3β/Fyn pathway and the enhancement of Nrf2 function were abolished in FGF21-null mice, confirming the critical role of FGF21 in FF-induced renal protection. These results suggest for the first time that FF prevents the development of DN via up-regulating FGF21 and stimulating PI3K/Akt/GSK-3β/Fyn-mediated activation of the Nrf2 pathway.
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DOI：
10.1056/nejmoa1306033
发表时间：
2013-12-26
期刊：
The New England journal of medicine
影响因子：
--
作者：
de Zeeuw D;Akizawa T;Audhya P;Bakris GL;Chin M;Christ-Schmidt H;Goldsberry A;Houser M;Krauth M;Lambers Heerspink HJ;McMurray JJ;Meyer CJ;Parving HH;Remuzzi G;Toto RD;Vaziri ND;Wanner C;Wittes J;Wrolstad D;Chertow GM;BEACON Trial Investigators
通讯作者：
BEACON Trial Investigators
影响因子：
--
作者：
Cai, L;Chen, SL;Chakrabarti, S
通讯作者：
Chakrabarti, S
影响因子：
4
作者：
Chen, Lu-Lu;Zhang, Jiao-Yue;Wang, Bao-Ping
通讯作者：
Wang, Bao-Ping
影响因子：
4.8
作者：
Jiang, Xin;Chen, Jun;Cai, Lu
通讯作者：
Cai, Lu
影响因子：
7.7
作者：
Jiang T;Huang Z;Lin Y;Zhang Z;Fang D;Zhang DD
通讯作者：
Zhang DD