PKR activation-induced mitochondrial dysfunction in HIV-transgenic mice with nephropathy
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.
Authors
- Briana A. Santo (ORCID: https://orcid.org/0000-0001-8850-2985)
- Khun Zaw Latt (ORCID: https://orcid.org/0000-0001-9754-8723)
- Komuraiah Myakala (ORCID: https://orcid.org/0000-0003-3233-047X)
- Cheryl Ann Winkler (ORCID: https://orcid.org/0000-0001-5552-0917)
- Yu Ishimoto (ORCID: https://orcid.org/0000-0001-5773-8637)
- Avi Z. Rosenberg (ORCID: https://orcid.org/0000-0003-2356-950X)
- Yongmei Zhao (ORCID: https://orcid.org/0000-0003-0800-4658)
- Pinaki Sarder (ORCID: https://orcid.org/0000-0003-2450-5233)
- Jeffrey B. Kopp (ORCID: https://orcid.org/0000-0001-9052-186X)
- Vincent M. Tutino (ORCID: https://orcid.org/0000-0002-1331-2551)
- Xiaoxin X. Wang (ORCID: https://orcid.org/0000-0001-9205-6228)
- Teruhiko Yoshida (ORCID: https://orcid.org/0000-0002-2049-7347)
- Moshe Levi (ORCID: https://orcid.org/0000-0001-6403-2261)
- Bryce A. Jones (ORCID: https://orcid.org/0000-0002-6950-8414)
- Koji Okamoto (ORCID: https://orcid.org/0000-0002-7601-6557)
- Shashi Shrivastav
- Xiaoping Yang (ORCID: https://orcid.org/0000-0003-1263-2710)
Institutions
- Johns Hopkins University (US)
- Georgetown University (US)
- University of Florida (US)
- National Institute of Diabetes and Digestive and Kidney Diseases (US)
- Tohoku University Hospital (JP)
- Frederick National Laboratory for Cancer Research (US)
- Jacobs (United States) (US)
- University at Buffalo, State University of New York (US)
Publication Details
- Journal
- eLife
- Published
- 2024-08-29
- DOI
- https://doi.org/10.7554/elife.91260.4
- Citations
- 1
- Primary Topic
- RNA regulation and disease
- Type
- article
- Field-Weighted Citation Impact
- 0.23
Funders
- National Institute of Diabetes and Digestive and Kidney Diseases