METTL3 aggravates renal fibrogenesis in obstructive nephropathy via the miR-199a-3p/PAR4 axis.

ABSTRACT

Renal fibrosis is among the major factors contributing to the development of chronic kidney disease. In this regard, although N6-methyladenosine (m6A) modification and micro-RNAs (miRNAs) have been established to play key roles in diverse physiological processes and disease/disorder development, further research is required to identify the probable mechanisms and processes associated with their involvement in renal fibrosis. In this study, we show that transforming growth factor ß1 (TGF-ß1)-induced human proximal tubule epithelial cells (HK2) are characterized by dose-dependently higher methyltransferase-like 3 (METTL3) expression. Furthermore, METTL3 was found to enhance pri-miR-199a-3p maturation and miR-199a-3p expression in an m6A-dependent manner, whereas miR-199a-3p sponges prostate apoptotic response 4 (Par4), thereby regulating its expression. Collectively, our findings in this study indicate that the METTL3/miR-199a-3p/Par4 axis plays a key role in the development of obstructive nephrogenic fibrosis.