Targeting oxidative stress-induced epigenetic reprogramming in fibrotic disease

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Project Summary of Parent funded R15 (1R15DK121362-01A1) The goal of this proposed study is to evaluate whether oxidative stress-induced epigenetic changes act as a driving factor for fibrosis in kidney. Multiple or repeated acute injuries to the kidney due to chronic exposure to toxicants lead to the development of kidney fibrosis, an irreversible disease for which there is no current treatment. Environmental toxicants are major risk factors for chronic kidney diseases. The generation of oxidative stress is the most common property of environmental toxicants. In addition to the exogenous sources of oxidative stress, the endogenous factors or basic characteristics of renal patients such as advanced age, diabetes and renal hypertension can also predispose the individuals to increasing levels of oxidative stress compared with the general population. In addition to genetic changes, the epigenetic mechanisms play an important role in transcriptional regulation of genes. However, the coordinated sequences of epigenetic alterations that drive oxidative stress-induced kidney fibrosis during CKD remain unknown. Our preliminary data revealed that persistent exposure to oxidative stress induces pEMT and induced pluripotent stem cell- like (iPSCs) feature, that are known to be associated with fibrosis. Based on preliminary data we hypothesize that “epigenetic reprogramming induced by pro-oxidant nephrotoxicants acts as a driver of cellular remodeling of kidney tubular epithelial cells through partial EMT and stemness leading to fibrogenesis”. To achieve the goal of this proposal, we will first Identify the temporal sequence and global distribution of epigenetic alterations during oxidative stress-induced fibrosis in kidney tubular epithelial cells using in vitro cell culture and in vivo animal models. Secondly, the role of epigenetic reprogramming of target genes for iPSCs and pEMT characteristics acquired by kidney epithelial cells and their impact on activation of fibroblast into ECM-producing myofibroblast will be determined. Finally, to evaluate the clinical significance of epigenetic therapy in inhibition of kidney fibrosis, we will evaluate whether reversal of epigenetic alterations in fibrotic kidney cells restores normal kidney epithelial characteristics and functions using in vitro and in vivo models. Kidney fibrosis is a well- established pathological stage in the development of CKD. This study will lead to a better understanding of the epigenetics-based molecular mechanism for oxidative stress-induced fibrosis during CKD. Identification of target molecules in kidney fibrosis will help to establish pharmacological interventions that could prevent the progression from acute tissue damage to an irreversible stage of fibrosis in the kidney and potentially in other target organs.