RIPK3 promotes G2/M cell cycle arrest in renal tubular epithelial cells for maladaptive kidney repair.

Maladaptive tubular repair is a key driver of renal fibrosis and the progression to chronic kidney disease (CKD) following acute kidney injury (AKI). Receptor-interacting protein kinase 3 (RIPK3) is involved in AKI and CKD via distinct mechanisms, but whether RIPK3 in renal tubular epithelial cells (RTECs) mediates maladaptive tubular repair after AKI remains unclear. We found that RIPK3 expression and activation were increased in RTECs from kidney tissues of patients who developed de novo CKD following cardiac surgery-associated AKI, as well as in an ischemia-reperfusion injury (IRI)-induced AKI-to-CKD transition mouse model. Importantly, both proximal RTEC-specific RIPK3 deletion and post-AKI treatment with RIPK3 inhibitor significantly attenuated renal fibrosis following AKI. Mechanistically, we demonstrated that RIPK3 inhibition alleviated G2/M cell cycle arrest in RTECs. RIPK3 interference reduced CDK1 phosphorylation at threonine 14, a key regulatory site for G2/M cell cycle arrest. Furthermore, combined knockdown of RIPK3 and CDK1 eliminated the decrease in G2/M phase arrest induced by RIPK3 silencing alone. Collectively, these findings identify a critical role for RIPK3 in maladaptive tubular repair after AKI, wherein it drives G2/M cell cycle arrest in RTECs by inhibiting CDK1 activity, and highlight the therapeutic potential of targeting RIPK3 to prevent maladaptive kidney repair.