Loss of Proximal Tubular Sirtuin 6 Aggravates Unilateral Ureteral Obstruction-Induced Tubulointerstitial Inflammation and Fibrosis by Regulation of β-Catenin Acetylation.
Loss of Proximal Tubular Sirtuin 6 Aggravates Unilateral Ureteral Obstruction-Induced Tubulointerstitial Inflammation and Fibrosis by Regulation of β-Catenin Acetylation.
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近端肾小管Sirtuin 6的缺失通过β-连环蛋白乙酰化的调节加重单侧输尿管梗阻诱导的肾小管间质炎症和纤维化
DOI：
10.3390/cells11091477
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发表时间：
2022-04-27
期刊：
影响因子：
6
通讯作者：
Kang, Kyung Pyo
中科院分区：
文献类型：
--
作者：
Jin, Jixiu;Li, Wenjia;Wang, Tian;Park, Byung-Hyun;Park, Sung Kwang;Kang, Kyung Pyo
肾纤维化是与进行性肾脏疾病相关的重要病理变化。Sirt 6是一种NAD+依赖性脱乙酰酶和单ADP核糖基转移酶，已知在衰老、代谢和致癌过程中发挥多种作用。然而，近端小管特异性Sirt 6在肾纤维化中的作用仍然难以捉摸。本研究探讨了近端肾小管特异性Sirt 6基因敲低对单侧输尿管梗阻（UUO）诱导的肾小管间质炎症和纤维化的影响。通过UUO手术诱导野生型和PT-Sirt 6 KO（Sirt 6 flox/flox; Ggt 1-Cre+）小鼠中的肾纤维化。7天后，进行组织学检查和Western印迹分析以检测细胞外基质（ECM）蛋白表达。我们评估了输尿管梗阻后炎症细胞因子和细胞粘附分子的表达。评估Sirt 6激活剂MDL-800对UUO诱导的肾小管间质炎症和纤维化的治疗效果。近端肾小管中Sirt 6的缺失加重了UUO诱导的肾小管损伤、ECM沉积、F4/80阳性巨噬细胞浸润以及促炎细胞因子和趋化因子表达。Sirt 6激活剂MDL-800减轻UUO诱导的肾小管间质炎症和纤维化。在体外实验中，MDL-800通过调节Sirt 6依赖性β-连环蛋白乙酰化和TGF-β1/Smad信号通路，降低转化生长因子（TGF）-β1诱导的肌成纤维细胞活化和ECM产生。结论：近端小管Sirt 6可能通过调节Sirt 6依赖的β-catenin乙酰化和ECM蛋白启动子转录，在UUO诱导的肾小管间质炎症和纤维化中发挥重要作用。
Renal fibrosis is a significant pathologic change associated with progressive kidney disease. Sirt6 is an NAD+-dependent deacetylase and mono-ADP ribosyltransferase known to play diverse roles in the processes attendant to aging, metabolism, and carcinogenesis. However, the role of proximal tubule-specific Sirt6 in renal fibrosis remains elusive. This study investigates the effect of proximal tubule-specific Sirt6 knockdown on unilateral ureteral obstruction (UUO)-induced renal tubulointerstitial inflammation and fibrosis. Renal fibrosis in wild type and PT-Sirt6KO (Sirt6flox/flox; Ggt1-Cre+) mice was induced by UUO surgery. After seven days, histologic examination and Western blot analysis were performed to examine extracellular matrix (ECM) protein expression. We evaluated inflammatory cytokine and cell adhesion molecule expression after ureteral obstruction. The therapeutic effect of Sirt6 activator MDL-800 on UUO-induced tubulointerstitial inflammation and fibrosis was assessed. The loss of Sirt6 in the proximal tubules aggravated UUO-induced tubular injury, ECM deposition, F4/80 positive macrophage infiltration, and proinflammatory cytokine and chemokine expression. Sirt6 activator MDL-800 mitigated UUO-induced renal tubulointerstitial inflammation and fibrosis. In an in vitro experiment, MDL-800 decreases the transforming growth factor (TGF)-β1-induced activation of myofibroblast and ECM production by regulating Sirt6-dependent β-catenin acetylation and the TGF-β1/Smad signaling pathway. In conclusion, proximal tubule Sirt6 may play an essential role in UUO-induced tubulointerstitial inflammation and fibrosis by regulating Sirt6-dependent β-catenin acetylation and ECM protein promoter transcription.
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DOI：
10.3904/kjim.2020.415
发表时间：
2021-05
期刊：
The Korean journal of internal medicine
影响因子：
--
作者：
Kim J;Park J
通讯作者：
Park J
Sirt6 缺陷通过靶向 Notch 信号传导加剧足细胞损伤和蛋白尿。
影响因子：
16.6
作者：
Liu M;Liang K;Zhen J;Zhou M;Wang X;Wang Z;Wei X;Zhang Y;Sun Y;Zhou Z;Su H;Zhang C;Li N;Gao C;Peng J;Yi F
通讯作者：
Yi F
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：
13.6
作者：
Maarouf, Omar H.;Aravamudhan, Anusha;Hunnphreys, Benjamin D.
通讯作者：
Hunnphreys, Benjamin D.
DOI：
10.1152/ajprenal.00255.2017
发表时间：
2017-09-01
影响因子：
4.2
作者：
Chuang, Peter Y.;Cai, Weijing;Lee, Kyung
通讯作者：
Lee, Kyung