Tubular-specific expression of HIV protein Vpr leads to severe tubulointerstitial damage accompanied by progressive fibrosis and cystic development

Yuqiang Chen, Ya Chen, Jia Fu, Zeguo Sun, Huilin Li, Wenzhen Xiao, Jing E, Benjamin Y. Lo, Niansong Wang, Weijia Zhang, Mary E. Klotman, Paul E. Klotman, Jeffrey B. Kopp, Vivette D. D'Agati, John Cijiang He, Kyung Lee

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Chronic kidney disease (CKD) is a common cause of morbidity in human immunodeficiency virus (HIV)-positive individuals. HIV infection leads to a wide spectrum of kidney cell damage, including tubular epithelial cell (TEC) injury. Among the HIV-1 proteins, the pathologic effects of viral protein R (Vpr) are well established and include DNA damage response, cell cycle arrest, and cell death. Several in vitro studies have unraveled the molecular pathways driving the cytopathic effects of Vpr in tubular epithelial cells. However, the in vivo effects of Vpr on tubular injury and CKD pathogenesis have not been thoroughly investigated. Here, we use a novel inducible tubular epithelial cell-specific Vpr transgenic mouse model to show that Vpr expression leads to progressive tubulointerstitial damage, interstitial inflammation and fibrosis, and tubular cyst development. Importantly, Vpr-expressing tubular epithelial cells displayed significant hypertrophy, aberrant cell division, and atrophy; all reminiscent of tubular injuries observed in human HIV-associated nephropathy (HIVAN). Single-cell RNA sequencing analysis revealed the Vpr-mediated transcriptomic responses in specific tubular subsets and highlighted the potential multifaceted role of p53 in the regulation of cell metabolism, proliferation, and death pathways in Vpr-expressing tubular epithelial cells. Thus, our study demonstrates that HIV Vpr expression in tubular cells is sufficient to induce HIVAN-like tubulointerstitial damage and fibrosis, independent of glomerulosclerosis and proteinuria. Additionally, as this new mouse model develops progressive CKD with diffuse fibrosis and kidney failure, it can serve as a useful tool to examine the mechanisms of kidney disease progression and fibrosis in vivo.

Original languageEnglish
Pages (from-to)529-543
Number of pages15
JournalKidney International
Volume103
Issue number3
DOIs
StatePublished - Mar 2023

Keywords

  • HIV-1 Vpr
  • apoptosis
  • cell cycle regulation
  • cystic kidney disease
  • proliferation
  • renal fibrosis
  • renal tubular epithelial cells

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