Angiotensin II receptor blocker attenuates intrarenal renin-angiotensin-system and podocyte injury in rats with myocardial infarction.
Angiotensin II receptor blocker attenuates intrarenal renin-angiotensin-system and podocyte injury in rats with myocardial infarction.
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血管紧张素 II 受体阻滞剂可减轻心肌梗死大鼠的肾内肾素血管紧张素系统和足细胞损伤
DOI：
10.1371/journal.pone.0067242
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Wang JF
中科院分区：
文献类型：
--
作者：
Wen ZZ;Cai MY;Mai Z;Jin DM;Chen YX;Huang H;Geng DF;Wang JF
心肌梗死（MI）后常见肾损害的机制和介质仍然知之甚少。本研究旨在验证血管紧张素II型1受体阻滞剂（ARBs）通过防止肾内肾素-血管紧张素系统（RAS）引起的足细胞损伤增强而在心肌梗死后发挥肾保护作用的假设。冠状动脉结扎术后的Sprague-Dawley大鼠分别给予氯沙坦（20mg /kg/d）或载药治疗3周或9周。评估肾功能、组织学和分子变化。目前的研究显示，在3周和9周时，mi诱导的肾小球足细胞损伤表现为desmin和p16ink4a免疫染色升高，Wilms ' tumor-1和podocin mRNA表达免疫染色降低，血胱抑素C升高。这些变化与肾内血管紧张素II水平升高、血管紧张素原mRNA和血管紧张素II受体mRNA和蛋白表达增强有关。这些变化还与9周时胰岛素样生长因子（IGF-1）水平下降、IGF-1受体（IGF-1R）蛋白、mRNA和磷酸化(p)-Akt蛋白表达下降以及8-羟基-2′-脱氧鸟苷表达增加有关。氯沙坦治疗显著降低desmin-和p16ink4a阳性足细胞，恢复足素mRNA表达，降低血胱抑素C水平。氯沙坦还能抑制RAS激活和氧化应激，恢复IGF-1/IGF-1R/Akt通路。综上所述，ARBs通过足细胞保护阻止心肌梗死后肾损害的进展，部分原因是通过抑制局部RAS的激活，从而增强氧化应激和抑制IGF-1/IGF-1R/Akt通路。
The mechanisms and mediators underlying common renal impairment after myocardial infarction (MI) are still poorly understood. The present study aimed to test the hypothesis that angiotensin II type 1 receptor blockers (ARBs) provides renoprotective effects after MI by preventing augmented intrarenal renin-angiotensin-system (RAS)-induced podocyte injury. Sprague–Dawley rats that underwent ligation of their coronary arteries were treated with losartan (20 mg/kg/d) or vehicle for 3 or 9 weeks. Renal function, histology and molecular changes were assessed. The current study revealed that MI-induced glomerular podocyte injury was identified by increased immunostaining for desmin and p16ink4a, decreased immunostaining for Wilms’ tumor-1 and podocin mRNA expression, and an induced increase of blood cystatin C at both 3 and 9 weeks. These changes were associated with increased intrarenal angiotensin II levels and enhanced expressions of angiotensinogen mRNA and angiotensin II receptor mRNA and protein. These changes were also associated with decreased levels of insulin-like growth factor (IGF-1) and decreased expressions of IGF-1 receptor (IGF-1R) protein and mRNA and phosphorylated(p)-Akt protein at 9 weeks, as well as increased expressions of 8-hydroxy-2’-deoxyguanosine at both time points. Treatment with losartan significantly attenuated desmin- and p16ink4a-positive podocytes, restored podocin mRNA expression, and decreased blood cystatin C levels. Losartan also prevented RAS activation and oxidative stress and restored the IGF-1/IGF-1R/Akt pathway. In conclusion, ARBs prevent the progression of renal impairment after MI via podocyte protection, partially by inhibiting the activation of the local RAS with subsequent enhanced oxidative stress and an inhibited IGF-1/IGF-1R/Akt pathway.
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影响因子：
2.5
作者：
Fujinaka, Hidehiko;Katsuyama, Koichi;Yamamoto, Tadashi
通讯作者：
Yamamoto, Tadashi
影响因子：
3
作者：
Niizuma, Shinichiro;Nakamura, Satoko;Kawano, Yuhei
通讯作者：
Kawano, Yuhei
影响因子：
19.6
作者：
Durvasula, RV;Petermann, AT;Shankland, SJ
通讯作者：
Shankland, SJ
影响因子：
10.8
作者：
SCHUNKERT, H;TANG, SS;INGELFINGER, JR
通讯作者：
INGELFINGER, JR
影响因子：
37.8
作者：
Rafiq K;Noma T;Fujisawa Y;Ishihara Y;Arai Y;Nabi AH;Suzuki F;Nagai Y;Nakano D;Hitomi H;Kitada K;Urushihara M;Kobori H;Kohno M;Nishiyama A
通讯作者：
Nishiyama A