The Genomic Response to TGF-β1 Dictates Failed Repair and Progression of Fibrotic Disease in the Obstructed Kidney.
The Genomic Response to TGF-β1 Dictates Failed Repair and Progression of Fibrotic Disease in the Obstructed Kidney.
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DOI：
10.3389/fcell.2021.678524
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发表时间：
2021
影响因子：
5.5
通讯作者：
Higgins PJ
中科院分区：
文献类型：
--
作者：
Higgins CE;Tang J;Higgins SP;Gifford CC;Mian BM;Jones DM;Zhang W;Costello A;Conti DJ;Samarakoon R;Higgins PJ
小管间质纤维化是一系列慢性肾脏疾病的常见诊断标志。虽然病因因潜在病理的致病性质而异，但持续的TGF-β1信号传导驱动肾纤维化疾病的无情进展。TGF-β1协调了肾纤维化的多方面过程，包括近端小管功能障碍、上皮恢复或再分化失败、毛细血管塌陷和随后的间质纤维化，最终导致慢性和终末期疾病。在TGF-β1信号传导过程中，非规范元素的补充增加作为辅助因子发挥作用。p53通过与TGF-β1受体激活的smad络合，是几种TGF-β1纤维化反应基因的转录共调节因子。这个协同p53/TGF-β1基因组簇包括参与细胞增殖控制、存活、凋亡、衰老和ECM重塑的基因。虽然这种相互依赖的分子基础仍有待确定，但TGF-β1调控基因的一个子集同时具有p53和smad结合基序。此外，p53表达和磷酸化的增加在各种形式的肾损伤和肾移植排斥反应中都很明显。通过药理学和遗传学方法靶向降低p53水平可减弱相关基因的表达并减轻纤维化反应，证实了p53在肾脏疾病中的关键作用。本综述主要关注TGF-β1在输尿管梗阻的背景下诱导肾纤维化的机制，输尿管梗阻模拟了儿童单侧输尿管肾盂连接梗阻的病理生理，以及p53在TGF-β1促纤维化基因库中作为转录调节因子的作用。
Tubulointerstitial fibrosis is a common and diagnostic hallmark of a spectrum of chronic renal disorders. While the etiology varies as to the causative nature of the underlying pathology, persistent TGF-β1 signaling drives the relentless progression of renal fibrotic disease. TGF-β1 orchestrates the multifaceted program of kidney fibrogenesis involving proximal tubular dysfunction, failed epithelial recovery or re-differentiation, capillary collapse and subsequent interstitial fibrosis eventually leading to chronic and ultimately end-stage disease. An increasing complement of non-canonical elements function as co-factors in TGF-β1 signaling. p53 is a particularly prominent transcriptional co-regulator of several TGF-β1 fibrotic-response genes by complexing with TGF-β1 receptor-activated SMADs. This cooperative p53/TGF-β1 genomic cluster includes genes involved in cellular proliferative control, survival, apoptosis, senescence, and ECM remodeling. While the molecular basis for this co-dependency remains to be determined, a subset of TGF-β1-regulated genes possess both p53- and SMAD-binding motifs. Increases in p53 expression and phosphorylation, moreover, are evident in various forms of renal injury as well as kidney allograft rejection. Targeted reduction of p53 levels by pharmacologic and genetic approaches attenuates expression of the involved genes and mitigates the fibrotic response confirming a key role for p53 in renal disorders. This review focuses on mechanisms underlying TGF-β1-induced renal fibrosis largely in the context of ureteral obstruction, which mimics the pathophysiology of pediatric unilateral ureteropelvic junction obstruction, and the role of p53 as a transcriptional regulator within the TGF-β1 repertoire of fibrosis-promoting genes.
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影响因子：
4.9
作者：
Bao YW;Yuan Y;Chen JH;Lin WQ
通讯作者：
Lin WQ
DOI：
10.1097/01.asn.0000067652.51441.21
发表时间：
2003-06-01
影响因子：
13.6
作者：
Bonventre, JV
通讯作者：
Bonventre, JV
DOI：
10.1159/000313738
发表时间：
2010-01-01
期刊：
CARDIORENAL SYNDROMES IN CRITICAL CARE
影响因子：
--
作者：
Bonventre, Joseph V.
通讯作者：
Bonventre, Joseph V.
DOI：
10.1073/pnas.1316177111
发表时间：
2014-01-28
影响因子：
11.1
作者：
Berger, Katja;Bangen, Joerg-Martin;Moeller, Marcus Johannes
通讯作者：
Moeller, Marcus Johannes
影响因子：
6.2
作者：
Anglicheau D;Muthukumar T;Hummel A;Ding R;Sharma VK;Dadhania D;Seshan SV;Schwartz JE;Suthanthiran M
通讯作者：
Suthanthiran M