Aebp1 drives a ceramide-gated Calhm2 calcium influx that injures podocytes in diabetic kidney disease.

INTRODUCTION Podocyte injury is a critical determinant of diabetic kidney disease (DKD) and other proteinuric nephropathies; however, the mechanisms linking lipotoxicity to cytoskeletal disruption remain unclear.

Objectives

This study aimed to identify a central regulator linking lipotoxicity to podocyte injury, decipher its downstream pathway to pathological calcium influx, and assess its translational potential as a non-invasive biomarker of disease progression.

Methods

Integrated transcriptomic-proteomic analysis of diabetic glomeruli identified Adipocyte Enhancer-Binding Protein 1 (Aebp1). Its function was investigated using renal overexpression and podocyte-specific knockout mouse models of diabetic and adriamycin (ADR) nephropathy. Mechanistic studies combined in vitro and in vivo analyses, including intracellular calcium kinetic assays and direct protein-lipid interaction assays (e.g., surface plasmon resonance). Clinical validation was conducted in a biopsy-proven DKD cohort, correlating urinary Aebp1 levels with histological severity and longitudinal estimated glomerular filtration rate (eGFR) decline.

Results

Aebp1 was identified as a progressively upregulated gene in the diabetic glomeruli. In mice, renal overexpression of Aebp1 induced proteinuria and glomerulosclerosis, whereas podocyte-specific knockout conferred protection against injury in diabetic mice. Mechanistically, Aebp1 activated NF-κB signaling, leading to Neu3 upregulation and pathogenic ceramide accumulation in the podocytes. We found that ceramide can directly bind to and activate Calhm2, a calcium channel not previously implicated in kidney physiology, suggesting a novel lipid-gated pathway linking lipotoxicity to pathological calcium influx in podocytes. This mechanism has been validated in ADR-induced nephropathy. Clinically, urinary Aebp1 serves as an independent predictor of histologically confirmed glomerulosclerosis severity and predicts the clinical endpoint of ≥ 30% eGFR decline.

Conclusion

This study identifies a potential pathway in which Aebp1 promotes ceramide accumulation which may activate the Calhm2 calcium channel, thus linking lipotoxicity to calcium dysregulation and podocyte injury in DKD and other proteinuric conditions. Urinary Aebp1 is a potential clinically non-invasive biomarker for predicting histological damage and functional decline in DKD.