Abstract: PO0899
Darunavir Protects Mice with Type 1 Diabetes Against Kidney Injury
Session Information
- Diabetic Kidney Disease: Basic Mechanisms
October 22, 2020 | Location: On-Demand
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
- Tandoh, Buadi K., Albert Einstein College of Medicine, Bronx, New York, United States
- Karttunen, Heidi, 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, HIV-positive persons still have increased risk of death and kidney disease and diabetes mellitus are important contributors to this excess mortality. Data from our laboratory demonstrate that the HIV protease inhibitor darunavir (DRV) prevents kidney disease in HIV-transgenic mice via mechanisms independent of HIV protease. Since diabetic kidney disease (DKD) is the most common cause of chronic kidney disease (CKD) in the general population and HIV infection predisposes persons with diabetes to more rapid progression of CKD, we studied the efficacy of DRV in a non-HIV animal model of DKD.
Methods
eNOS-/- 9 week-old C57BL/6 mice underwent induction of diabetes by administration of 5 daily 50mg/kg doses of streptozotocin (STZ) injection. Blood glucose was measured before and after DRV treatment. 14 weeks after STZ induction, mice were treated with either DRV (100mg/kg) or control by daily oral gavage for 4 weeks. Albumin-to-creatinine ratio (ACR) assay, immunocytochemistry, western blotting and real-Time PCR were performed with routine protocols. Mouse blood pressure (BP) was measured with CODA mouse tail-cuff system.
Results
STZ induced severe sustained hyperglycemia in eNOS-/- mice, which resulted in marked increase urine ACR. DRV-treated mice had a 60% decrease in UACR compared to control-treated mice but blood glucose levels did not change. DRV also reduced renal fibrosis as detected by tubulointerstitial type 1 collagen and fibronectin and prevented loss of synaptopodin expression in podocytes. Since the renin-angiotensin system (RAS) is an important contributor to DKD pathogenesis, we studied whether DRV affected expression of RAS genes. Unexpectedly, DRV increased renin expression and ACE expression in kidneys of diabetic eNOS -/- mice to levels similar to non-diabetic mice. DRV also increased endothelial CD31 and VEGFR2 expression in glomeruli, but did not change renal VEGF expression in diabetic eNOS-/- mice. Surprisingly, DRV treatment reduced mean BP in diabetic eNOS-/- mice.
Conclusion
These data demonstrate that DRV protects mice against type I diabetic renal injury. Further studies are needed to determine whether changes to renal gene expression are due to direct effects of DRV or secondary to reduced renal injury, resulting in normalization of gene expression suppression and BP.
Funding
- NIDDK Support