Inhibition of GRK2 mitigates renal fibrosis via oxidative stress pathway.

BACKGROUND

Studies have shown that G protein-coupled receptor kinase 2 (GRK2) undergoes functional changes in various diseases. Therefore, in this study, we examined the role of GRK2 in renal fibrosis induced by unilateral ureteral occlusion (UUO) and ischaemia-reperfusion (I/R), and evaluated the protective effect of pharmacological inhibition of GRK2.

METHODS

UUO or I/R models were generated in GRK2 knockdown (GRK2-KD), GRK2 conditional-knockdown (GRK2-CKd), and wild-type (WT) mice. Biochemical markers of renal function and histopathological features of renal tissues were evaluated to assess the extent of renal fibrosis and the protective effect of pharmacological GRK2 inhibition. Transforming growth factor beta (TGF-β) and hypoxia-reoxygenation (H/R) models were established in GRK2 knockout (GRK2-KO) cells in vitro.

RESULTS

The UUO/I/R model mice exhibited pathological damage and increased expression of GRK2 and NADPH oxidase 4 (NOX4). Compared to the Control group, the GRK2-KD and GRK2-CKd groups presented notable amelioration of renal function and pathological features, reduced NOX4 and oxidative stress. In vitro studies revealed that knocking out GRK2 reduced NOX4 levels, ameliorated oxidative stress, moderated cellular epithelial-mesenchymal transition (EMT), improved levels of collagen Ⅰ, α-smooth muscle actin (α-SMA), and E-cadherin, as well as the cellular morphology. In addition, pharmacological treatment with GRK2-inhibitors (CP-25 or paroxetine) markedly improved UUO/I/R-induced fibrosis.

CONCLUSIONS

Pharmacologically blocking GRK2 using CP-25 or paroxetine effectively alleviates renal fibrosis by regulating NOX4 and oxidative stress. GRK2 represents a potential target for the prevention and treatment of renal fibrosis and inflammation.