Tubular-Specific Expression of HIV Protein Vpr Leads to Severe Tubulointerstitial Damage Accompanied by Progressive Fibrosis and Cystic Development

Authors

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

Publication Date

3-1-2023

Journal

Kidney International

DOI

10.1016/j.kint.2022.12.012

PMID

36565808

PMCID

PMC9974916

PubMedCentral® Posted Date

3-1-2024

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Animals, Humans, Mice, AIDS-Associated Nephropathy, Disease Models, Animal, Gene Products, vpr, HIV Infections, HIV-1, Human Immunodeficiency Virus Proteins, Mice, Transgenic, Renal Insufficiency, Chronic, HIV-1 Vpr, renal tubular epithelial cells, proliferation, cell cycle regulation, apoptosis, renal fibrosis, cystic kidney disease

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.

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