Abstract: PO0691
The HIV Protease Inhibitor Darunavir Protects Against Diabetic Kidney Injury in Mice and Alters Stress Granule-Associated Signaling
Session Information
- Diabetic Kidney Disease: Basic - II
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 601 Diabetic Kidney Disease: Basic
Authors
- Gao, Xiaobo, Albert Einstein College of Medicine, Bronx, New York, United States
- Sonia, Fnu, Albert Einstein College of Medicine, Bronx, New York, United States
- Karttunen, Heidi, Albert Einstein College of Medicine, Bronx, New York, United States
- Tandoh, Buadi, Albert Einstein College of Medicine, Bronx, New York, United States
- Ross, Michael J., Albert Einstein College of Medicine, Bronx, New York, United States
Background
Despite the success of antiretroviral therapy (ART) in improving mortality, persons living with HIV (PLWH) still have increased risk of death and kidney disease and diabetes mellitus are important contributors to this excess mortality. Previously published studies in our laboratory demonstrated that the HIV protease inhibitor darunavir (DRV) prevents kidney injury via mechanisms that are independent of HIV protease but the mechanisms by which DRV protects against renal injury remain unclear. Studies in our lab found that DRV binds to several stress granule (SG) associated proteins, including G3BP1. SG are membraneless organelles composed of translationally arrested mRNAs and ribonucleoproteins and have important roles in stress and injury responses.
Methods
Diabetes was induced in 9-week-old eNOS-/- C57BL/6 mice by administration of 5 daily 50 mg/kg doses of streptozotocin (STZ). 14 weeks later, mice were treated with either DRV (100mg/kg) or control by daily oral gavage for 4 weeks. Urinary albumin-to-creatinine ratio (UACR) assay, immunofluorescence (IF) microscopy, western blotting and real-time PCR were performed according to routine protocols in our laboratory. For in vitro studies, human proximal tubular cells (HPT1b) at 40-60% confluence were transfected with Accell siRNA for G3BP1 in Accell Delivery Media.
Results
STZ induced severe hyperglycemia and kidney injury in eNOS-/- mice, which resulted in marked increase in UACR. DRV treatment markedly reduced UACR, attenuated tubulointerstitial fibrosis as detected by type 1 collagen and fibronectin, and prevented loss of podocyte synaptopodin and endothelial CD31 expression in glomeruli as detected by IF. IF studies also demonstrated that G3BP1 and phosphorylation of Stat3, Src, and Erk were increased in the kidneys of diabetic eNOS-/- mice and these changes were reduced by DRV treatment. To directly test the role of G3BP1 in promoting Stat3, Src, and Erk phosphorylation, we used siRNA to knock down G3BP1 expression in human tubular cells, which reduced phosphorylation of Stat3, Src and Erk.
Conclusion
These data suggest that DRV prevents diabetes-induced kidney injury in mice in part, via interactions with the SG protein G3BP1. Additional studies are needed to further delineate the effects of targeting SG function upon diabetic kidney injury.
Funding
- NIDDK Support