Presentation description

Diabetic kidney disease (DKD) is a leading cause of chronic kidney disease (CKD) and end stage renal failure, with evidence pointing to ceramide overload as a key driver. Ceramides, a class of sphingolipids, are involved in lipotoxicity, mitochondrial dysfunction, and inflammation in DKD. While previous studies have focused on specific ceramide species, the broader consequences of generalized ceramide overproduction in kidney cells remain less explored. We investigated whether podocyte specific overexpression of serine palmitoyltransferase (SPT), an early rate limiting enzyme in ceramide synthesis, leads to glomerular injury and worsens DKD progression. Using a Cre Lox system, we developed transgenic mice that overexpress SPT specifically in podocytes, ensuring that ceramide overexpression is exclusive to kidney tissue. We evaluated three groups of mice: heterozygous overexpressors at 24 weeks of age following streptozotocin (STZ) induced diabetes, heterozygous overexpressors at 24 weeks of age without STZ treatment, and homozygous overexpressors. Measurements included albumin creatinine ratio (ACR), expression of kidney injury and fibrosis markers (Lcn2, Fn1, TNF-α), and glomerular histology. Heterozygous overexpressors without STZ treatment exhibited elevated ACR and increased expression of inflammatory and fibrotic markers. Homozygous overexpressors experienced early mortality (4 weeks) and showed severe glomerular injury consistent with ceramide induced podocyte toxicity.These results suggest that even moderate ceramide elevation in podocytes can impair renal function, and that high levels may lead to rapid disease progression. Podocyte specific ceramide overproduction recapitulates key features of DKD and exacerbates disease in diabetic conditions. This model provides valuable insight into the function of ceramide driven glomerular injury and supports the development of ceramide targeted therapies in DKD.