The progression of obstructive renal fibrosis in rats is regulated by ADAMTS18 gene methylation in the embryonic kidney through the AKT/Notch pathway

Abstract

AbstractThis study aimed to explore the mechanism by which postembryonic renal ADAMTS18 methylation influences obstructive renal fibrosis in rats. After exposure to transforming growth factor (TGF)‐β1 during the embryonic period, analysis of postembryonic renal ADAMTS18 methylation and expression levels was conducted. Histological analysis was performed to assess embryonic kidney lesions and damage. Western blot analysis was used to determine the expression of renal fibrosis markers. Rats with ureteral obstruction and a healthy control group were selected. The methylation levels of ADAMTS18 in the different groups were analyzed. Western blot analysis and immunohistochemistry were performed to analyze the expression of renal fibrosis markers, and kidney‐related indicators were measured. Treatment with TGF‐β1 resulted in abnormal development of the postembryonic kidney, which was characterized by rough kidney surfaces with mild depressions and irregularities on the outer surface. TGF‐β1 treatment significantly promoted ADAMTS18 methylation and activated the protein kinase B (AKT)/Notch pathway. Ureteral obstruction was induced to establish a renal hydronephrosis model, which led to renal fibrotic injury in newborn rats. Overexpression of the ADAMTS18 gene alleviated renal fibrosis. The western blot results showed that compared to that in the control group, the expression of renal fibrosis markers was significantly decreased after ADAMTS18 overexpression, and there was a thicker renal parenchymal tissue layer and significantly reduced p‐AKT/AKT and Notch1 levels. TGF‐β1 can induce ADAMTS18 gene methylation in the postembryonic kidney, and the resulting downregulation of ADAMTS18 expression has long‐term effects on kidney development, potentially leading to increased susceptibility to obstructive renal fibrosis. This mechanism may involve activation of the AKT/Notch pathway. Reversing ADAMTS18 gene methylation may reverse this process.