CerS6 links ceramide metabolism to innate immune responses in diabetic kidney disease

Ectopic lipid deposition, mitochondrial injury, and inflammatory responses contribute to the development of diabetic kidney disease (DKD); however, the mechanistic link between these processes remains unclear. In this study, we demonstrate that the ceramide synthase 6 (CerS6) is primarily localized in podocytes of the glomeruli and is upregulated in two different models of diabetic mice. Podocyte-specific CerS6 knockout ameliorates glomerular injury and inflammatory responses in male diabetic mice and in male mice with adriamycin-induced nephropathy. In contrast, podocyte-specific overexpression of CerS6 sufficiently induces proteinuria. Mechanistically, CerS6-derived ceramide (d18:1/16:0) can bind to the mitochondrial channel protein VDAC1 at Glu59 residue, initiating mitochondrial DNA (mtDNA) leakage, activating the cGAS-STING signaling pathway, and ultimately promoting an immune-inflammatory response in the kidney. Importantly, CERS6 expression is increased in podocytes from kidney biopsies of patients with DKD and focal segmental glomerulosclerosis (FSGS), and the expression level of CERS6 is correlated negatively with glomerular filtration rate and positively with proteinuria. Thus, our findings suggest that targeting CerS6 may be a potential therapeutic strategy for proteinuric kidney diseases.