PKR activation-induced mitochondrial dysfunction in HIV-transgenic mice with nephropathy

• Published in: eLife Vol. 12
• Main Authors: Yoshida, Teruhiko, Latt, Khun Zaw, Rosenberg, Avi Z, Santo, Briana A, Myakala, Komuraiah, Ishimoto, Yu, Zhao, Yongmei, Shrivastav, Shashi, Jones, Bryce A, Yang, Xiaoping, Wang, Xiaoxin X, Tutino, Vincent M, Sarder, Pinaki, Levi, Moshe, Okamoto, Koji, Winkler, Cheryl A, Kopp, Jeffrey B
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 29.08.2024; eLife Sciences Publications Ltd; eLife Sciences Publications, Ltd
• Subjects: AIDS-Associated Nephropathy - genetics; AIDS-Associated Nephropathy - metabolism; AIDS-Associated Nephropathy - pathology; Animals; Approximation; Cell activation; Chronic kidney failure; Creatinine; Cyclin-dependent kinases; Cytoskeleton; Disease Models, Animal; Double-stranded RNA; eIF-2 kinase; eIF-2 Kinase - genetics; eIF-2 Kinase - metabolism; Gene expression; Genes; Genetic engineering; Genomes; HIV; HIV (Viruses); HIV-1 - genetics; HIV-1 - physiology; HIV-associated nephropathy; Human immunodeficiency virus; Humans; Kidney diseases; Kinases; Medicine; Mice; Mice, Transgenic; Mitochondria; Mitochondria - metabolism; Mitochondrial DNA; Morbidity; Nephropathy; Neutrophils; Oxidative phosphorylation; Phenotypes; Phosphorylation; Platelet-derived growth factor; Podocytes - metabolism; Principal components analysis; protein kinase R; Proteins; Proximal tubules; Quantitative analysis; RNA; RNA-seq; Scientific equipment and supplies industry; single-nucleus RNA-seq; Stat3 protein; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Transgenic mice; Canada; United States; California; United States > US; HIV-associated nephropathy; mouse; HIV; RNA-seq; mitochondria; medicine; single-nucleus RNA-seq; protein kinase R
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.91260

HIV disease remains prevalent in the USA and chronic kidney disease remains a major cause of morbidity in HIV-1-positive patients. Host double-stranded RNA (dsRNA)-activated protein kinase (PKR) is a sensor for viral dsRNA, including HIV-1. We show that PKR inhibition by compound C16 ameliorates the HIV-associated nephropathy (HIVAN) kidney phenotype in the Tg26 transgenic mouse model, with reversal of mitochondrial dysfunction. Combined analysis of single-nucleus RNA-seq and bulk RNA-seq data revealed that oxidative phosphorylation was one of the most downregulated pathways and identified signal transducer and activator of transcription (STAT3) as a potential mediating factor. We identified in Tg26 mice a novel proximal tubular cell cluster enriched in mitochondrial transcripts. Podocytes showed high levels of HIV-1 gene expression and dysregulation of cytoskeleton-related genes, and these cells dedifferentiated. In injured proximal tubules, cell-cell interaction analysis indicated activation of the pro-fibrogenic PKR-STAT3-platelet-derived growth factor (PDGF)-D pathway. These findings suggest that PKR inhibition and mitochondrial rescue are potential novel therapeutic approaches for HIVAN.