Li Lu'an, Li Jiaying, Li Ruizhao, Zhao Xingchen, Chen Yuanhan, Cai Yating, Yang Yan, Wang Weiteng, Zheng Siqi, Zhang Li, Liang Xinling
Department of Nephrology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, China.
Adv Sci (Weinh). 2025 Jun 20:e03325. doi: 10.1002/advs.202503325.
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.
受体相互作用蛋白激酶3（RIPK3）是坏死性凋亡的关键因子和新兴的炎症调节因子，其在糖尿病肾病（DKD）中对足细胞损伤的作用尚不清楚。在此，利用足细胞特异性RIPK3基因敲除（KO）的DKD小鼠和高糖（HG）培养的小鼠足细胞，以阐明足细胞RIPK3缺失对DKD的保护作用，探索RIPK3在足细胞损伤中的分子致病机制，并评估抑制RIPK3信号传导作为一种治疗策略的效果。结果表明，足细胞特异性RIPK3-KO可减轻DKD小鼠的蛋白尿、系膜基质增生、足突融合和足细胞丢失。此外，在DKD肾活检中足细胞RIPK3上调，且表达与蛋白尿呈负相关。在体外，使用小干扰RNA（siRNA）敲低RIPK3或用GSK'872抑制可预防足细胞损伤。对小鼠足细胞进行RNA测序显示，敲低RIPK3可减轻HG诱导的NF-κB相关炎症通路的激活。重要的是，GSK'872对RIPK3的药理抑制减轻了足细胞损伤，并降低了DKD小鼠的蛋白尿。总体而言，这些结果揭示了足细胞RIPK3通过独立于坏死性凋亡调节NF-κB介导的炎症信号传导在促进足细胞损伤和DKD进展中的新作用，为DKD的管理提供了新的见解和潜在的治疗策略。
