Transcriptomics reveal dysregulated genes during folic acid-induced acute injury and fibrosis in kidney and their attenuation by antioxidant N-acetyl cysteine.

Renal fibrosis is a common pathogenic stage during the progression of acute injury to chronic kidney disease. Pathophysiological changes such as cellular remodeling, dysregulation of fibrogenic signaling, and extracellular matrix contribute to kidney fibrosis. Oxidative stress is a common feature of nephrotoxicants. However, the target molecules and mechanistic pathways dysregulated by oxidative stress during acute injury and fibrosis in kidney are not fully understood. Therefore, the objective of this study was to identify the target molecules altered by oxidative stress and determine whether the antioxidant N-acetyl cysteine can attenuate acute injury and long-term fibrosis in kidney. Both in vitro cell culture and in vivo mice models were used to address these questions. Multiple approaches, such as serum creatinine-albumin levels, histopathological, immunohistochemical, transcriptome analysis by RNA-sequencing, and target-specific expression of fibrogenic marker genes for cellular remodeling and fibrogenic signaling, were used to evaluate the role of oxidative stress in acute kidney injury (AKI) and kidney fibrosis. Novel findings of this study not only revealed that antioxidants can protect from acute injury and attenuate fibrosis in kidney by abrogating oxidative stress-induced cellular remodeling, activated profibrogenic genes, and signaling pathways, but also identified several target genes and signaling molecules, including those associated with kidney function and extracellular matrix regulation that were previously not known to be associated with AKI and kidney fibrosis. Findings of this study have significance in understanding the pathophysiological effects of nephrotoxicant-induced oxidative stress in kidney fibrosis and the roles of dysregulated genes in the etiology of this disease.NEW & NOTEWORTHY Using both in vitro and in vivo models, this study suggests that antioxidants can protect from acute injury and attenuate fibrosis in kidney by abrogating oxidative stress-induced partial-EMT, activated profibrogenic genes, and signaling pathways including TGF-β, Wnt, and Notch signaling. Transcriptome analysis identified several previously unknown fibrosis-associated gene transcripts, and further investigation is needed to understand their precise roles in the etiology of this disease.