Apolipoprotein C-III Deficiency Mediates Podocyte Injury in Glomerular Diseases

Background: Emerging evidence suggests that impaired cholesterol efflux and lipid droplet (LD) accumulation in podocytes contribute to the pathogenesis of glomerular diseases. Apolipoprotein C-III (APOCIII), a small protein associated with lipid storage organelles within the lumen of the endoplasmic reticulum—referred to as lumenal LDs—is a potent inhibitor of triglyceride lipolysis and the hepatic clearance of triglyceride-rich lipoproteins. APOCIII undergoes glycosylation and sialylation, resulting in the formation of functionally distinct isomers: ApoC-III0, ApoC-III1, and ApoC-III2. We hypothesize that reduced podocyte APOCIII expression and impaired sialylation contribute to cytoplasmic LD accumulation and lipotoxicity-induced podocyte injury. Methods: Publicly available RNA-Seq datasets from CKD, DKD, and Alport Syndrome patients were analyzed for APOCIII expression. The expression of APOCIII and sialylation-related proteins was determined by qRT-PCR and Western blotting in immortalized podocytes derived from Col4a3+/+ (IMWT) and Col4a3-/- (IMAS) mice, as well as in kidney cortices of Col4a3+/+ mice and Col4a3-/- mice, a model of progressive glomerular disease. Immunofluorescence staining was performed to assess APOCIII localization in IMWT and IMAS podocytes. Results: APOCIII expression was significantly decreased in glomeruli of patients with various glomerular diseases. Protein expression of total glycosylated APOCIII and APOCIII2 was significantly reduced in podocytes and kidney cortices of Col4a3-/- mice. In IMWT podocytes, APOCIII exhibited strong, perinuclear staining and co-localized with the Golgi apparatus, whereas in IMAS podocytes APOCIII staining was reduced and primarily associated with LDs. Sialylation-related proteins including CMP-sialic acid synthetase (CMAS), Neuraminidase 1 (NEU1), and solute carrier family 35 member A1 (SLC35A1) were not significantly altered in IMAS podocytes. However, ST3 Beta-Galactoside Alpha-2,3-Sialyltransferase 1 (ST3GAL1), the enzyme responsible for terminal sialylation of glycoproteins and glycolipids, was significantly reduced in both podocytes and kidney cortices of Col4a3-/- mice. Conclusion: Our findings suggest a potential role for reduced APOCIII expression and sialylation in lipotoxicity-induced podocyte injury. Funding: NIDDK Support