ASN's Mission

To create a world without kidney diseases, the ASN Alliance for Kidney Health elevates care by educating and informing, driving breakthroughs and innovation, and advocating for policies that create transformative changes in kidney medicine throughout the world.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

Abstract: TH-PO202

The HIV Protease Inhibitor Darunavir Restores Autophagy in Kidneys of Diabetic Mice

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Ross, Michael J., Albert Einstein College of Medicine, Bronx, New York, United States
  • Karttunen, Heidi, Albert Einstein College of Medicine, Bronx, New York, United States
  • Gao, Xiaobo, Albert Einstein College of Medicine, Bronx, New York, United States
Background

Despite the success of antiretroviral therapy (ART) in improving mortality, persons with HIV have increased risk of death, and kidney disease and diabetes are important contributors to their 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 and also reduces albuminuria and molecular markers of kidney injury in mice with diabetic kidney disease (DKD). Since autophagy is cytoprotective against HIV and diabetes-induced kidney injury, and autophagy is reduced in the kidneys of patients with DKD, we studied the effect of DRV upon autophagy in a murine model of DKD.

Methods

eNOS-/- 9 week-old C57BL/6 mice, which develop more severe nephropathy than wild-type C57BL/6 mice, underwent induction of diabetes by administration of 5 daily 50mg/kg doses of streptozotocin (STZ) injection. 14 weeks after diabetes induction, mice were treated with either DRV (100mg/kg) or control by daily oral gavage for 4 weeks. Urinary albumin creatinine ratio (ACR) assay, immunocytochemistry, western blotting and real-time PCR were performed with routine protocols in our laboratory.

Results

STZ induced severe sustained hyperglycemia and kidney injury in eNOS-/- mice, which resulted in marked increase urine ACR, which was reduced by DRV. Western blotting and immunfluorescence studies demonstrated marked accumulation of lipidated LC3 (LC3-II) and p62 in kidneys of diabetic eNOS-/- mice, indicating reduced autophagic flux. Accumulation of LC3-II and p62 in diabetic eNOS-/- kidneys was most apparent in tubular cells. DRV treatment reduced LC3-II and p62 in diabetic eNOS-/- mice to levels that were similar to non-diabetic mice.

Conclusion

Kidneys of diabetic eNOS-/- mice had reduced autophagic flux (accumulated LC3-II and p62) compared to non-diabetic mice, which was reversed by DRV. Our previous studies demonstrated that DRV reduced albuminuria and molecular markers of glomerular and tubular injury in mice with DKD. Our data suggest that DRV may protect against DKD via normalization of autophagic flux. Since reducing albuminuria may affect autophagy in tubular cells, future studies will determine whether the effect of DRV upon autophagy is independent of its effects on albuminuria.

Funding

  • NIDDK Support