Increasing cGMP-dependent protein kinase activity attenuates unilateral ureteral obstruction-induced renal fibrosis

被引:30
作者
Cui, Wenpeng [2 ,3 ]
Maimaitiyiming, Hasiyeti [1 ,2 ]
Qi, Xinyu [1 ,2 ]
Norman, Heather [1 ,2 ]
Zhou, Qi [1 ,2 ]
Wang, Xiaojun [2 ]
Fu, Jian [4 ]
Wang, Shuxia [1 ,2 ]
机构
[1] Lexington Vet Affairs Med Ctr, Lexington, KY USA
[2] Univ Kentucky, Grad Ctr Nutr Sci, Lexington, KY 40536 USA
[3] Jilin Univ, Hosp 2, Dept Nephrol, Changchun 130023, Peoples R China
[4] Univ Kentucky, Ctr Res Environm Dis, Grad Ctr Toxicol, Lexington, KY 40536 USA
基金
美国国家卫生研究院;
关键词
PKG; UUO; renal fibrosis; TGF-beta; 1; INTERSTITIAL FIBROSIS; KIDNEY; INHIBITION; SILDENAFIL; MECHANISMS; EXPRESSION; INJURY; MODEL; RATS;
D O I
10.1152/ajprenal.00657.2013
中图分类号
Q4 [生理学];
学科分类号
071003 ;
摘要
Our previous studies support the protective effect of cGMP and cGMP-dependent protein kinase I (PKG-I) pathway on the development of renal fibrosis. Therefore, in the present studies, we determined whether pharmacologically or genetically increased PKG activity attenuates renal fibrosis in a unilateral ureteral obstruction (UUO) model and also examined the mechanisms involved. To increase PKG activity, we used the phosphodiesterase 5 inhibitor sildenafil and PKG transgenic mice. UUO model was induced in wild-type or PKG-I transgenic mice by ligating the left lateral ureteral and the renal fibrosis was observed after 14 days of ligation. Sildenafil was administered into wild-type UUO mice for 14 days. In vitro, macrophage and proximal tubular cell function was also analyzed. We found that sildenafil treatment or PKG transgenic mice had significantly reduced UUO-induced renal fibrosis, which was associated with reduced TGF-beta signaling and reduced macrophage infiltration into kidney interstitial. In vitro data further demonstrated that both macrophages and proximal tubular cells were important sources of UUO-induced renal TGF-beta levels. The interaction between macrophages and tubular cells contributes to TGF-beta-induced renal fibrosis. Taken together, these data suggest that increasing PKG activity ameliorates renal fibrosis in part through regulation of macrophage and tubular cell function, leading to reduced TGF-beta-induced fibrosis.
引用
收藏
页码:F996 / F1007
页数:12
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