Podocyte RIPK3 Deletion Improves Diabetic Kidney Disease by Attenuating NF-κB p65 Driven Inflammation.

Receptor-interacting protein kinase 3 (RIPK3) is a key player in necroptosis and an emerging inflammation regulator, whose contribution to podocyte injury in diabetic kidney disease (DKD) remain unclear. Here, podocyte-specific RIPK3-knockout (KO) DKD mice and high glucose (HG) cultured mouse podocytes are used to elucidate the protective effects of podocyte RIPK3 deletion on DKD, explore the molecular pathogenic mechanisms of RIPK3 in podocyte injury, and assess pharmacological inhibition of RIPK3 signaling as a therapeutic strategy. The results demonstrated that podocyte-specific RIPK3-KO alleviated albuminuria, mesangial matrix proliferation, foot process fusion, and podocyte loss in DKD mice. Additionally, podocyte RIPK3 is upregulated in renal biopsies with DKD and expression is negatively correlated with albuminuria. In vitro, knockdown of RIPK3 using small interfering RNA (siRNA) or inhibition with GSK'872 prevented podocyte injury. RNA sequencing of mouse podocytes revealed that the knockdown of RIPK3 can alleviate HG-induced activation of the NF-κB-related inflammatory pathways. Importantly, pharmacological inhibition of RIPK3 by GSK'872 alleviated podocyte damage, and reduced proteinuria in DKD mice. Overall, these results uncovered a novel role of podocyte RIPK3 in promoting podocyte injury and DKD progression by regulating NF-κB-mediated inflammatory signaling independent of necroptosis, offering novel insights and potential therapeutic strategies for DKD management.