Epigenetic Modifications in Renal Fibrogenesis

描述（申请人提供）：肾纤维化是慢性肾脏疾病的标志，是临床肾脏病学的一个突出问题。与急性肾损伤的生理性修复不同，进行性肾纤维化是一个独立的持续过程，即使最初的损伤已经消除，也不会停止。活化的成纤维细胞是纤维化的主要介质，从纤维化肾脏分离的成纤维细胞在体外培养时甚至不能恢复到静止状态。这种持续的成纤维细胞活化的分子机制尚不清楚。在全基因组甲基化筛选中，我们发现Ras抑制剂RASAL1是纤维化肾成纤维细胞中甲基化的13个基因之一，但在非纤维化肾成纤维细胞中没有甲基化。这项拨款申请的中心假设是，“肾成纤维细胞中Ras原癌基因的抑制因子RASAL1的高甲基化阻止了它们回到静止状态，并使纤维形成的进程持续下去”。基于初步数据，我们将阐明RASAL1的高甲基化是否通过Ras的过度活跃导致成纤维细胞的持续激活，最终导致肾纤维化。公共卫生相关性：肾纤维化是临床肾脏病学中的一个主要问题，因为它会导致肾功能进行性丧失，需要透析或肾移植来避免立即死亡。临床上还没有特定的治疗方法来阻止甚至逆转，这使得对潜在的病理机制有了进一步的了解。纤维化类似于伤口修复。然而，与伤口修复不同的是，一旦最初的损伤得到控制，纤维生成就不会停止，从而导致永久性疤痕组织的形成，从而导致肾衰竭。一些患者的纤维化过程不能停止的原因尚不清楚。这一应用将阐明表观遗传变化在肾纤维化中的作用，表观遗传变化是相对稳定的DNA修饰。

DESCRIPTION (provided by applicant): Renal fibrosis is the hallmark of chronic kidney disease, a prominent problem in clinical nephrology. Unlike physiologic repair of acute kidney injury, progressive renal fibrosis is a self-contained perpetuated process, which fails to cease even when the initial insult has been eliminated. Activated fibroblasts are the main mediators of fibrosis, and fibroblasts isolated from fibrotic kidneys even fail to return to their quiescent state when cultured in vitro. The molecular mechanisms that underlie this persisting fibroblast activation are not yet known. In a genomewide methylation screen we identified the Ras inhibitor RASAL1 as one of 13 genes to be methylated in fibroblasts from fibrotic kidneys, but not in fibroblasts from non-fibrotic kidneys. The central hypothesis of this grant application is that 'hypermethylation of RASAL1, a suppressor of the Ras proto-oncogene, in renal fibroblasts prevents them from returning to their quiescent state and perpetuates progression of fibrogenesis". Based on the preliminary data we will elucidate if hypermethylation of RASAL1 causes perpetuated fibroblast activation via Ras hyperactivity, ultimately leading to renal fibrosis. PUBLIC HEALTH RELEVANCE: Renal fibrosis is a major problem in clinical Nephrology, because it causes progressive loss of kidney function, requiring dialysis or kidney transplantation to circumvent instant fatality. Specific therapies to halt - or even reverse - are not yet available in the clinic, making further understanding of the underlying pathomechanisms relevant. Fibrosis resembles wound repair. However, unlike wound repair, fibrogenesis does not cease once the initial insult has been contained, causing perpetuated scar tissue formation which results in kidney failure. The reason why the fibrotic process fails to stop in some patients is not known. This application will elucidate the role of epigenetic changes, which are relatively stable modifications of DNA, in renal fibrosis.