Abstract: FR-PO422
Role of CD13 in Renal Proximal Tubular Handling of Albumin
Session Information
- Diabetic Kidney Disease: Basic - II
October 26, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 601 Diabetic Kidney Disease: Basic
Authors
- Lo, Robin H., University of Connecticut School of Medicine, Farmington, Connecticut, United States
- Gerber, Claire, University of Connecticut School of Medicine, Farmington, Connecticut, United States
- Shearier, Emily R., University of Connecticut School of Medicine, Farmington, Connecticut, United States
- Ghosh, Mallika, University of Connecticut School of Medicine, Farmington, Connecticut, United States
- Shapiro, Linda H., University of Connecticut School of Medicine, Farmington, Connecticut, United States
Background
Albuminuria, a complication of disease states that damage glomerular function such as diabetic nephropathy (DN), promotes renal damage by triggering pro-inflammatory and pro-fibrotic pathways leading to chronic kidney disease (CKD). Understanding how the kidney handles urinary albumin may thus be beneficial for identifying therapeutic mechanisms to limit disease progression. Urinary proteins are normally efficiently resorbed via the Megalin-Cubilin receptor complex and the neonatal Fc Receptor (FcRn) in the proximal tubule. CD13, a multifunctional cell surface molecule, negatively regulates clathrin-dependent endocytosis in various cell types. Like the albumin endocytic receptors, CD13 is expressed abundantly on the apical surface of proximal tubule epithelial cells. Here, we examined the role of CD13 in renal proximal tubular handling of albumin in two murine models of albuminuria as well as in unchallenged mice.
Methods
WT and CD13 KO C57/B16 mice were used for both a streptozotocin (STZ) induced DN model (50 mg/kg daily for 5 days) and albumin overload (AO) model (bovine serum albumin; increasing daily doses from 2 mg/g to 10 mg/g on day 5, final 10 mg/g dose on day 8). Urine and serum were collected at basal, 8, 12, 16, and 20 weeks post STZ-treatment in the DN model and day 8 in the AO model for ELISA analysis. Kidneys were collected for immunofluorescence, flow cytometry, and electron microscopy analysis. Relationship of CD13 to Megalin, Cubilin, and FcRn was analyzed by co-immunofluorescence of kidney sections and western blotting of brush border membrane fractions.
Results
Compared to WT, CD13 KO mice exhibited significantly decreased albuminuria in both 20 week STZ-induced DN and AO models, as well as increased cellular uptake of albumin in the proximal tubules even in unchallenged conditions. Furthermore, we identified possible mechanisms by which CD13 regulates albumin endocytosis, including 1) co-localization of CD13 and FcRn, 2) elevated levels of cubilin at the brush border of CD13 KO proximal tubules, and 3) maintenance of cristae integrity in CD13 KO mitochondria after 20 week STZ-induced DN.
Conclusion
Our results suggest that CD13 serves as a key mediator for albumin endocytosis in the proximal tubule and may be a potential therapeutic target for preventing albuminuria-induced damage in renal disease.
Funding
- Other NIH Support