S100A1 Promotes MDM2 ‐Mediated KLF15 Ubiquitination to Regulate ID1 ‐Driven Tubular Injury in Diabetic Kidney Disease

ABSTRACT Diabetic kidney disease (DKD) is the leading cause of end‐stage renal disease globally. Tubular injury represents an early pathological hallmark of DKD and a core driver of disease progression. By comparing single‐cell RNA sequencing (scRNA‐seq) data of kidney samples from healthy controls and DKD patients, we found significantly upregulated S100 calcium‐binding protein A1 (S100A1) expression in the proximal tubules of DKD patients, while its role and regulatory mechanism in DKD pathogenesis remain largely unclear. Analysis of renal biopsy specimens from DKD patients showed that S100A1 was markedly upregulated in proximal tubules, and its expression level was significantly correlated with 24‐h proteinuria, serum creatinine, and estimated glomerular filtration rate (eGFR). In vitro, S100A1 promoted tubular injury, inflammatory cytokine release, and fibrotic responses in high glucose‐stimulated human proximal tubular epithelial cells (HK‐2). Mechanistically, S100A1 enhanced the interaction between E3 ubiquitin ligase MDM2 and transcription factor Krüppel‐like factor 15 (KLF15), induced K48‐linked ubiquitination and proteasomal degradation of KLF15, relieved KLF15‐mediated transcriptional repression of inhibitor of DNA binding 1 (ID1), and ultimately aggravated tubular injury. In vivo, proximal tubule‐specific knockdown of S100A1 attenuated renal injury, inflammatory infiltration, and fibrosis in diabetic mice. Our findings reveal a novel S100A1‐MDM2‐KLF15‐ID1 regulatory axis in DKD pathogenesis. Targeting S100A1 might be a potential therapy for proximal tubular injury in DKD.