Targeting of G protein-coupled receptor 39 alleviates angiotensin II-induced renal damage by reducing ribonucleotide reductase M2.

ABSTRACT

Renal fibrosis, apoptosis and autophagy are the main pathological manifestations of angiotensin II (Ang II)-induced renal injury. G protein-coupled receptor 39 (GPR39) is highly expressed in various tissues including the kidney, but its role in the kidney is entirely unclear. This study was performed to investigate the underlying mechanism by which knockdown of GPR39 alleviated Ang II-induced renal injury. In vivo, GPR39 knockout (KO) mice were constructed and infused with Ang II for 4 weeks, followed by renal function tests. In vitro, Ang II-induced cells were treated with si-GPR39 for 48 h. Fibrosis, apoptosis and autophagy were detected in both cells and mice. The underlying mechanism was sought by mRNA transcriptome sequencing and validated in vitro. GPR39 was upregulated in renal tissues of mice with Ang II-mediated renal injury. Knockdown of GPR39 ameliorated renal fibrosis, apoptosis, and autophagy, and decreased the expression of ribonucleotide reductase M2 (RRM2). In vitro, knockdown of GPR39 was also identified to improve the Ang II-induced cell fibrosis, apoptosis, and autophagy. mRNA transcriptome results showed that knockout of GPR39 reduced the expression of RRM2 in Ang II-induced kidney tissue. Activation of RRM2 could reverse the therapeutic effect of GPR39 knockout, and the inhibitor of RRM2 could improve the cell fibrosis, apoptosis and autophagy caused by GPR39 agonist. These results indicated that targeting of GPR39 could alleviate Ang II-induced renal fibrosis, apoptosis, and autophagy via reduction of RRM2 expression, and GPR39 may serve as a potential target for Ang II-induced renal injury.