Abstract: SA-PO375
Novel Role for Albumin and Its Modifications in Podocyte and Glomerular Injury
Session Information
- Glomerular Diseases: Immunology and Inflammation - III
October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1202 Glomerular Diseases: Immunology and Inflammation
Authors
- Agrawal, Shipra, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
- Kino, Jiro, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
- Kitao, Tetsuya, Nationwide Children's Hospital, Columbus, Ohio, United States
- Chanley, Melinda A., Nationwide Children's Hospital, Columbus, Ohio, United States
- Smoyer, William E., Nationwide Children's Hospital, Columbus, Ohio, United States
Background
Albuminuria is both a characteristic hallmark and a known risk factor for progressive glomerular disease. We previously identified that both albumin deficiency and albumin overload resulted in enhanced glomerular injury. We thus hypothesized that glomerular and podocyte injury can be regulated by modifications of albumin levels, binding to free fatty acid (FFA) and associated factors, and molecular charge.
Methods
In vitro podocyte injury was studied following exposure to native albumin (anionic), delipidated albumin, FFA, and cationic albumin. The ability of plasmapheresis effluents (PE) from nephrotic patients to induce podocyte injury in vivo and in vitro was also analyzed. Additional analyses included testing the ability of various clinically applicable matrices to ameliorate albumin- and PE-induced podocyte injury.
Results
While exposure of podocytes to albumin or FFA (lauric acid, oleic acid and arachidonic acid) alone reduced podocyte viability, supplementation of FFA with delipidated albumin restored podocyte viability. Albumin exposure also activated the kinases p38 MAPK, JNK/SAPK and AKT. While arachidonic acid and delipidated albumin alone did not activate these kinases, activation was moderately increased when podocytes were exposed to their combination. Additionally, cationic albumin induced greater podocyte toxicity vs. albumin, even at 1000x lower concentration. Translational studies in nephrotic PE revealed diverse signs of direct podocyte injury, including reduced viability, actin cytoskeletal disruption, lipid accumulation, activation of Erk1/2 and JNK/SAPK, and induction of COX-2. Importantly, some of these responses were attenuated by pretreatment of PE with selected matrices (charcoal, blue sepharose, liposorber gel and dextran sulfate). Finally, compared to the albumin alone-treated rats, we found significantly greater albuminuria at 48 hr in rats also injected with nephrotic PE.
Conclusion
Albumin modifications, including altered levels, binding to FFA and associated factors, and altered ionic charge can regulate albumin-induced podocyte and glomerular injury. Moreover, treatment with clinically applicable matrices appears to be able reduce this injury, thus representing a potential novel mechanistic approach to reduce glomerular injury and disease progression.