Kidney Week

Abstract: TH-PO0355

Apolipoprotein C-III Deficiency Mediates Podocyte Lipotoxicity in Glomerular Diseases

Session Information

• Glomerular Diseases: Genetics to Therapeutics
  October 22, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology

Authors

• Njeim, Rachel, University of Miami Miller School of Medicine, Miami, Florida, United States

Rachel Njeim, PharmD, PhD

• Insenga, Arianna, University of Miami Miller School of Medicine, Miami, Florida, United States

Arianna Insenga

• Tolerico, Matthew, University of Miami Miller School of Medicine, Miami, Florida, United States

Matthew Tolerico

• Fontanella, Antonio Miguel, University of Miami Miller School of Medicine, Miami, Florida, United States

Antonio Miguel Fontanella

• Zevola, Mario, University of Miami Miller School of Medicine, Miami, Florida, United States

Mario Zevola, PhD

• Molina David, Judith T., University of Miami Miller School of Medicine, Miami, Florida, United States

Judith T. Molina David, PhD

• Mitrofanova, Alla, University of Miami Miller School of Medicine, Miami, Florida, United States

Alla Mitrofanova, PhD

• Merscher, Sandra, University of Miami Miller School of Medicine, Miami, Florida, United States

Sandra Merscher, PhD

• Fornoni, Alessia, University of Miami Miller School of Medicine, Miami, Florida, United States

Alessia Fornoni, MD, PhD, FASN

Background

Increasing evidence implicates impaired cholesterol efflux and lipid droplet (LD) accumulation in podocytes in the pathogenesis of glomerular diseases (GDs). 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 hepatic clearance of triglyceride-rich lipoproteins. APOCIII undergoes glycosylation and sialylation, resulting in the formation of distinct isomers: APOCIII₀, APOCIII₁, and APOCIII₂. 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 patients were analyzed to assess APOCIII expression. Plasma APOCIII levels were measured in patients with focal segmental glomerulosclerosis (FSGS) and in Col4a3^-/- mice, a model of progressive GD. APOCIII and sialylation-related enzymes were evaluated in bulk RNA-sequencing data from immortalized murine podocytes derived from Col4a3^+/+ (IMWT) and Col4a3^-/- (IMAS) mice, and further assessed by Western blotting in IMWT and IMAS podocytes as well as in kidney cortices from Col4a3^+/+ and Col4a3^-/- mice.

Results

APOCIII expression was significantly decreased in glomeruli of patients with GDs, while plasma APOCIII levels were increased in patients with FSGS. Plasma APOCIII was elevated in Col4a3^-/- mice, whereas the protein expression of total glycosylated APOCIII and APOCIII₂ was significantly reduced in podocytes and kidney cortices from Col4a3^-/- mice. Reduced APOCIII expression and decreased co-localization with the Golgi, along with increased PLIN2 expression, were observed in podocytes isolated from Col4a3^-/- mice, suggesting increased cytosolic rather than lumenal LD accumulation and impaired APOCIII sialylation. Consistently, ST3GAL1, the enzyme responsible for terminal sialylation of glycoproteins, 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. Future experiments will include human podocytes with APOCIII knockdown (shAPOCIII) and scrambled control (shCtrl) to evaluate apoptosis and LD accumulation and distribution following treatment with oleic acid.

Funding

• NIDDK Support