Abstract: FR-PO225

Darunavir Protects HIV-Transgenic Mice against Kidney Injury via HIV-Independent Mechanisms

Session Information

Category: Cell Biology

  • 202 Apoptosis, Proliferation, Autophagy, Cell Senescence, Cell Transformation

Authors

  • Gao, Xiaobo, Albert Einstein College of Medicine/ Montefiore Medical Center, Hastings-on-Hudson, New York, United States
  • Rosales, Alan, Albert Einstein College of Medicine/ Montefiore Medical Center, Hastings-on-Hudson, New York, United States
  • Karttunen, Heidi, Albert Einstein College of Medicine/ Montefiore Medical Center, Hastings-on-Hudson, New York, United States
  • Ross, Michael J., Albert Einstein College of Medicine/ Montefiore Medical Center, Hastings-on-Hudson, New York, United States
Background

HIV-associated nephrology (HIVAN) is characterized by severe proteinuria and progressive CKD and is caused by infection of renal epithelial cells, though active viral replication is not necessary to induce disease in animal and in vitro models. Antiretroviral therapy (ART) markedly reduces the risk of progression to ESRD without eradicating HIV in the kidney and the mechanism(s) by which ART protects kidneys from HIVAN is poorly understood.

Methods

We studied HIV-transgenic mice, which develop a HIVAN phenotype. Since the transgene in these mice does not encode HIV Reverse Transcriptase (RT) or Protease we used these mice to determine if the HIV protease inhibitor darunavir (DRV) and/or RT inhibitor zidovidine (AZT) protect against HIVAN independent of effects on RT or HIV protease. Mice were treated for 4 weeks by daily oral gavage in 4 groups: DRV (100mg/kg), AZT (50mg/kg), DRV+AZT, or control.

Results

DRV and DRV+AZT, but not AZT alone reduced urinary albumin:creatinine ratio and histologic glomerular and tubulointerstitial injury. DRV and DRV+AZT, but not AZT also markedly reduced expression of the proliferation marker Ki67 in tubular cells, prevented loss of synaptopodin expression in podocytes, and reduced phosphorylation of ERK1,2, and Stat3, which are important mediators of HIV-induced kidney injury.
To further examine the mechanism of DRV-induced protection, we studied the effects of DRV renal tubular epithelial cells (RTEC) transduced with gag/pol-deleted HIV lentivirus (lacking HIV protease and RT), HIV Vpr-expressing lentivirus, or control lentivirus. DRV significantly attenuated HIV and Vpr-induced activation of Stat3, ERK, and Src and decreased HIV and Vpr-induced expression of IL-6 and IL-8, which are key inflammatory mediators in HIVAN.

Conclusion

These data demonstrate that DRV but not AZT protects against HIV-induced renal injury via mechanisms that are at least partly independent of suppression of HIV replication and HIV Protease. Additional studies are needed to identify the non-HIV molecular targets of DRV which mediate these effects and to determine the efficacy in non-HIV related kidney diseases.

Funding

  • NIDDK Support