ZyVersa Therapeutics highlights data on role of lipotoxicity in DKD

ZyVersa Therapeutics (ZVSA) highlights key data on the role of lipotoxicity in the development and progression of DKD from a review article, Targeting lipid metabolic reprogramming to alleviate diabetic kidney disease: molecular insights and therapeutic strategies, recently published in Frontiers in Immunology. This article, which summarized 172 papers, demonstrated that under diabetic conditions, kidney cells undergo significant lipid metabolic abnormalities resulting in accumulation of lipids that trigger inflammation and fibrosis leading to DKD progression. Metabolic issues associated with diabetes, especially insulin resistance and high blood glucose, lead to abnormal lipid metabolism resulting in kidney lipid accumulation, inflammation, and fibrosis. Multiple impaired pathways contribute to lipid accumulation: Insulin resistance increases release of free fatty acids and uptake by kidney cells; Activation of fatty acid synthesis pathways leads to excessive lipid production; Impaired cholesterol efflux resulting from reduced function of cholesterol transporters, ABCA1 and ABCG1, leads to cholesterol and lipid accumulation; Impaired fatty acid oxidation, reduces ability to break down and use stored lipids. Of the above pathways, impaired cholesterol efflux is a key factor in DKD pathology. It exacerbates lipid accumulation, especially in podocytes, the key component of the kidney’s filtration system, causing structural damage and impaired filtration resulting in protein leaking into the urine, DKD progression, and ultimately kidney failure, if the lipotoxicity is not addressed. Lipid overload can trigger an inflammasome-induced inflammatory response in kidney cells. Free fatty acids activate inflammasomes initiating an inflammatory cascade via release of IL-1beta. Inflammasome activation also induces upregulation of lipid synthesis-related genes while inhibiting expression of lipid efflux transporters like ABCA1, further increasing lipid accumulation. This creates a vicious cycle, causing continuous decline in renal function and ultimately causes irreversible damage. Currently, no drugs specifically target kidney lipotoxicity.