Leung Janet Y, Wilson Harper L, Voltzke Kristin J, Williams Lindsay A, Lee Hyo Jin, Wobker Sara E, Kim William Y
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Mol Cell Biol. 2017 May 31;37(12). doi: 10.1128/MCB.00565-16. Print 2017 Jun 15.
Tubulointerstitial fibrosis (TIF) is recognized as a final phenotypic manifestation in the transition from chronic kidney disease (CKD) to end-stage renal disease (ESRD). Here we show that conditional inactivation of in the mouse renal epithelium resulted in upregulated expression of profibrotic genes and TIF. Loss of induced Stat3 activation and a senescence-associated secretory phenotype (SASP) that coincided with the development of tubulointerstitial fibrosis. Treatment of mice with the YAP inhibitor verteporfin (VP) inhibited activation of genes associated with senescence, SASPs, and activation of Stat3 as well as impeded the development of fibrosis. Collectively, our studies offer novel insights into molecular events that are linked to fibrosis development from loss and implicate VP as a potential pharmacological inhibitor to treat patients at risk for developing CKD and TIF.
肾小管间质纤维化（TIF）被认为是慢性肾脏病（CKD）向终末期肾病（ESRD）转变的最终表型表现。在此，我们表明在小鼠肾上皮细胞中条件性失活导致促纤维化基因表达上调和TIF。的缺失诱导了Stat3激活以及与衰老相关的分泌表型（SASP），这与肾小管间质纤维化的发展相一致。用YAP抑制剂维替泊芬（VP）治疗小鼠可抑制与衰老、SASP相关基因的激活以及Stat3的激活，并阻碍纤维化的发展。总体而言，我们的研究为与缺失导致纤维化发展相关的分子事件提供了新的见解，并表明VP作为一种潜在的药理抑制剂可用于治疗有发展为CKD和TIF风险的患者。
