Caloric restriction ameliorates kidney ischaemia/reperfusion injury through PGC-1-eNOS pathway and enhanced autophagy
Caloric restriction ameliorates kidney ischaemia/reperfusion injury through PGC-1-eNOS pathway and enhanced autophagy
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DOI：
10.1111/apha.12120
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发表时间：
2013-08-01
影响因子：
6.3
通讯作者：
Mervaala, E. M.
中科院分区：
文献类型：
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作者：
Lempiainen, J.;Finckenberg, P.;Mervaala, E. M.
目的：我们研究了热量限制（CR）预处理是否能改善肾缺血/再灌注（I/R）损伤，以及CR的有益作用是否通过增强自噬和/或激活关键代谢传感器SIRT1、amp激酶和PGC-1介导。方法：将6 ~ 7周龄Wistar大鼠分为3组：(i)假手术组；（ii） I/R组（缺血40 min后再灌注24h）；（iii） I/R组术前2周保持CR（能量摄入70%）。在另外的实验中，sirtinol和3-甲基腺嘌呤（3-MA）分别作为SIRT1和自噬的抑制剂。测定肾功能，并对急性肾小管损伤及硝基酪氨酸表达进行评分。检测肾腺苷单磷酸活化激酶（AMPK）、SIRT1、eNOS、PGC-1、LC-3B的表达。结果：热量限制可改善肾功能，防止急性肾小管坏死的发生，减轻I/ r诱导的亚硝化应激。肾I/R损伤使eNOS和PGC-1表达降低，自噬抑制，SIRT1和AMPK表达分别增加2.6倍和4倍。然而，AMPK的磷酸化水平降低。与I/R损伤组相比，CR进一步使肾脏SIRT1表达增加了1.8倍，促进了自噬，抵消了I/R诱导的eNOS和PGC-1表达的下降。3-MA消除了CR的肾保护作用，而sirtinol对I/R损伤CR大鼠的肾功能没有影响。结论：热量限制通过增强自噬和抵消I/R诱导的肾eNOS和PGC-1表达的降低来改善急性肾I/R损伤。
Aim: We investigated whether preconditioning with caloric restriction (CR) ameliorates kidney ischaemia/reperfusion (I/R) injury and whether the salutary effects of CR are mediated through enhanced autophagy and/or activation of key metabolic sensors SIRT1, AMP-kinase and PGC-1.Methods: Six- to seven-week-old Wistar rats were divided into three groups: (i) sham-operated group; (ii) I/R group (40-min ischaemia followed by 24h of reperfusion); and (iii) I/R group kept under CR (energy intake 70%) for 2weeks before surgery. In additional experiments, sirtinol and 3-methyladenine (3-MA) were used as inhibitors of SIRT1 and autophagy respectively. Renal function was measured, and acute tubular damage and nitrotyrosine expression were scored. Kidney adenosine monophosphate-activated kinase (AMPK), SIRT1, eNOS, PGC-1 and LC-3B expressions were measured.Results: Caloric restriction improved renal function, protected against the development of acute tubular necrosis and attenuated I/R-induced nitrosative stress. Kidney I/R injury decreased eNOS and PGC-1 expression, inhibit autophagy and increased SIRT1 and AMPK expressions by 2.6- and fourfold respectively. However, phosphorylation level of AMPK was decreased. As compared with I/R injury group, CR further increased kidney SIRT1 expression by 1.8-fold, promoted autophagy and counteracted I/R-induced decreases in the expression of eNOS and PGC-1. 3-MA abolished the renoprotective effects of CR, whereas sirtinol did not influence renal function in CR rats with I/R injury.Conclusions: Caloric restriction ameliorates acute kidney I/R injury through enhanced autophagy and counteraction of I/R-induced decreases in the renal expression of eNOS and PGC-1.