Poricoic acid A suppresses renal fibroblast activation and interstitial fibrosis in UUO rats via upregulating Sirt3 and promoting β-catenin K49 deacetylation  

作　　者：Dan-Qian Chen Lin Chen Yan Guo Xia-Qing Wu Ting-Ting Zhao Hai-Ling Zhao Hao-Jun Zhang Mei-Hua Yan Guo-Qiang Zhang Ping Li 

机构地区：[1]Department of Emergency,China-Japan Friendship Hospital,Beijing 100029,China [2]Faculty of Life Science&Medicine,Northwest University,Xi’an 710069,China [3]Department of Internal Medicine,University of New Mexico,Albuquerque,NM 87131,USA [4]Beijing Key Lab for Immune-Mediated Inflammatory Diseases,Institute of Clinical Medical Sciences,China-Japan Friendship Hospital,Beijing 100029,China

出　　处：《Acta Pharmacologica Sinica》2023年第5期1038-1050,共13页中国药理学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(Grant No.82104511,82174296);the Project funded by China Postdoctoral Science Foundation(Grant No.2021M693579);the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(GrantNo:ZYYCXTD-C-202005).

摘　　要：Renal interstitial fibrosis is the common pathological process of various chronic kidney diseases to end-stage renal disease.Inhibition of fibroblast activation attenuates renal interstitial fibrosis.Our previous studies show that poricoic acid A(PAA)isolated from Poria cocos is a potent anti-fibrotic agent.In the present study we investigated the effects of PAA on renal fibroblast activation and interstitial fibrosis and the underlying mechanisms.Renal interstitial fibrosis was induced in rats or mice by unilateral ureteral obstruction(UUO).UUO rats were administered PAA(10 mg·kg^(−1)·d^(−1),i.g.)for 1 or 2 weeks.An in vitro model of renal fibrosis was established in normal renal kidney fibroblasts(NRK-49F cells)treated with TGF-β1.We showed that PAA treatment rescued Sirt3 expression,and significantly attenuated renal fibroblast activation and interstitial fibrosis in both the in vivo and in vitro models.In TGF-β1-treated NRK-49F cells,we demonstrated that Sirt3 deacetylatedβ-catenin(a key transcription factor of fibroblast activation)and then accelerated its ubiquitin-dependent degradation,thus suppressing the protein expression and promoter activity of pro-fibrotic downstream target genes(twist,snail1,MMP-7 and PAI-1)to alleviate fibroblast activation;the lysine-49(K49)ofβ-catenin was responsible for Sirt3-mediatedβ-catenin deacetylation.In molecular docking analysis,we found the potential interaction of Sirt3 and PAA.In both in vivo and in vitro models,pharmacological activation of Sirt3 by PAA significantly suppressed renal fibroblast activation via facilitatingβ-catenin K49 deacetylation.In UUO mice and NRK-49F cells,Sirt3 overexpression enhanced the anti-fibrotic effect of PAA,whereas Sirt3 knockdown weakened the effect.Taken together,PAA attenuates renal fibroblast activation and interstitial fibrosis by upregulating Sirt3 and inducingβ-catenin K49 deacetylation,highlighting Sirt3 functions as a promising therapeutic target of renal fibroblast activation and interstitial fibrosis.

关 键 词：renal interstitial fibrosis sirt3 poricoic acid A Β-CATENIN DEACETYLATION fibroblast activation unilateral ureteral obstruction(UUO) 

分 类 号：R285.5[医药卫生—中药学]