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Abstract: SA-PO974

Human Immunodeficiency Virus Vpr Induces Severe Tubulointerstitial Damage With Progressive Fibrosis and Cystic Development

Session Information

  • CKD: Pathobiology - II
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2203 CKD (Non-Dialysis): Mechanisms


  • Fu, Jia, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Sun, Zeguo, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Zhang, Weijia, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Kopp, Jeffrey B., National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
  • D'Agati, Vivette D., Columbia University, New York, New York, United States
  • He, John Cijiang, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Lee, Kyung, Icahn School of Medicine at Mount Sinai, New York, New York, United States

HIV-positive individuals are at increased risk for CKD and ESKD. HIV leads to a wide spectrum of glomerular and tubulointerstitial injuries, but molecular pathways by which HIV injures kidney cells are partly understood. Experimental mouse studies have implicated the key roles of Nef and Vpr in HIVAN pathogenesis. These studies also indicated that tubulointerstitial injury and inflammation occur secondary to glomerular injury, whereas human studies suggested a direct effect of HIV on tubular cells. In vitro studies demonstrated a salient role of Vpr on tubular injury, where Vpr induces DNA damage response, cell cycle arrest, and cytokinesis defects, resulting in apoptosis and polyploidy in a majority of cells and hyperproliferation in small subsets. To elucidate the pathogenic effects of Vpr in tubular injury in HIVAN, we examined the consequence of tubular Vpr expression in mice.


We generated mice expressing Pax8-rtTA and TetO-Vpr transgenes, which were induced with doxycycline (Pax8-Vpr). Histopathologic and marker analyses of tubular injury, fibrosis, cell cycle regulators, and apoptosis were performed in Pax8-Vpr kidneys over time. scRNAseq of Pax8-Vpr kidneys was performed to elucidate the pathways altered in Vpr-injured kidneys.


Tubular Vpr expression led to progressive tubular atrophy, diffuse tubulointerstitial inflammation, and fibrosis, which were accompanied by prominent cortical cysts and kidney failure, but without proteinuria. Tubular cells of Pax8-Vpr kidneys displayed significant DNA damage and aberrant cell division, consistent with previous in vitro findings. scRNAseq analysis showed changes consistent with impairments in mitochondrial function and fatty acid oxidation and activation of various cell death pathways including ferroptosis in specific tubular cell subsets. Other subsets of tubular cells showed changes consistent with cell cycle deregulation and proliferation, suggestive of mechanisms involved in the expansion of cystic cells.


Our study demonstrates for the first time that the induction of an HIV gene specifically in tubular cells leads to severe tubulointerstitial injury and fibrosis, independent of HIV-mediated glomerulosclerosis and proteinuria. It also demonstrates tubular cell-specific gene expression changes induced by Vpr and its consequences in vivo.


  • NIDDK Support