Obesity Augments Necroinflammation and Worsens Injury With Folic Acid‐Induced Acute Kidney Injury

Acute kidney injury (AKI) involves necrotic damage to the renal tubular epithelium accompanied by inflammation and cell death-a pattern referred to as necroinflammation. Obesity, a global health crisis, stimulates chronic low-grade inflammation; however, its influence on AKI is not well understood. We examined folic acid-induced AKI (FA-AKI) in obese mice fed a high-fat diet (HFD) for 6 weeks, compared to mice on a control diet (CD). Following FA-AKI, obese HFD mice showed significantly higher serum urea and creatinine, more severe morphological injury, and greater expression of the injury marker NGAL. RT-PCR revealed that AKI with obesity increased inflammation, evidenced by increased Il6 and Ccl2 mRNA expression. Tubular vacuolation and Oil Red O staining revealed tubular cell lipid accumulation with HFD. Higher levels of receptor-interacting protein kinase-3 (RIPK3) mRNA and protein were seen in FA-AKI mice on the HFD, in association with significantly increased expression of phosphorylated mixed lineage kinase domain-like protein (pMLKL), the key trigger of necroptotic cell death, in tubular epithelium. While FA-AKI altered ferroptosis markers (e.g., Acsl4 ↓, Gpx4 ↑), these changes were unaffected by HFD. Apoptosis markers were increased by FA-AKI but unaffected by HFD, and similarly, markers of autophagic flux were altered by FA-AKI but not significantly changed by HFD. In summary, these data reveal worsened AKI and increased necroinflammation in obese mice, with increased activation of necroptosis. These descriptive findings add to current evidence for the importance of necroinflammation in AKI and suggest necroptosis may be a key obesity-sensitive process in renal injury, identifying these as potential therapeutic targets in obese AKI patients.