Targeting inflammation and necroptosis in diabetic kidney disease: A novel approach via PPARα modulation

Renal tubular interstitial inflammation is a central driver of the pathogenesis of diabetic kidney disease (DKD). Peroxisome proliferator-activated receptor alpha (PPARα), predominantly expressed in renal tubular epithelial cells (TECs), plays a key role in regulating inflammation. However, the precise molecular mechanisms through which PPARα exerts its protective effects in DKD remain unclear.

Single-cell RNA sequencing data from the GEO database revealed a marked reduction in PPARα expression in the proximal TECs of early-stage DKD patients. To investigate its potential role, we utilized an AAV9-PPARα viral vector to induce PPARα overexpression in TECs within a DKD mouse model. RNA sequencing of kidney tissues from both DKD and PPARα-overexpressing DKD mice was performed to identify key differentially expressed genes and signaling pathways. These findings were subsequently validated by in vitro and in vivo experiments.

PPARα overexpression significantly improved renal function, reduced interstitial fibrosis, attenuated inflammatory cytokine expression, and markedly decreased M1 macrophage infiltration. Notably, PPARα inhibited RIP1/RIP3/MLKL-mediated necroptosis in TECs, resulting in a substantial delay in DKD progression. Furthermore, NF-κB signaling played a crucial role in PPARα-mediated regulation of inflammation and necroptosis in TECs.

In summary, PPARα plays a pivotal role in modulating inflammation and necroptosis in DKD. Targeting PPARα in TECs represents a promising therapeutic strategy for slowing the progression of DKD and potentially reversing early renal damage. These findings open up new avenues for PPARα-targeted therapies in DKD and other chronic kidney diseases.