{"doi":"10.7554/elife.91260.1","title":"PKR activation-induced mitochondrial dysfunction in HIV-transgenic mice with nephropathy","abstract":"Abstract 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 and were lost from the glomerular tuft. In injured proximal tubules, cell-cell interaction analysis indicated activation of the profibrogenic 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.","journal":null,"year":2023,"id":401481,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9569,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":445010,"name":"Khun Zaw Latt","orcid":"0000-0001-9754-8723","position":1,"is_corresponding":false},{"id":235991,"name":"Avi Z. Rosenberg","orcid":"0000-0003-2356-950X","position":2,"is_corresponding":false},{"id":820099,"name":"Briana A. Santo","orcid":"0000-0001-8850-2985","position":3,"is_corresponding":false},{"id":344474,"name":"Komuraiah Myakala","orcid":"0000-0003-3233-047X","position":4,"is_corresponding":false},{"id":997408,"name":"Yu Ishimoto","orcid":"0000-0001-5773-8637","position":5,"is_corresponding":false},{"id":228426,"name":"Yongmei Zhao","orcid":"0000-0003-0800-4658","position":6,"is_corresponding":false},{"id":921186,"name":"Shashi Shrivastav","orcid":null,"position":7,"is_corresponding":false},{"id":328130,"name":"Bryce A. Jones","orcid":"0000-0002-6950-8414","position":8,"is_corresponding":false},{"id":768127,"name":"Xiaoping Yang","orcid":"0000-0003-1263-2710","position":9,"is_corresponding":false},{"id":344473,"name":"Xiaoxin X. Wang","orcid":"0000-0001-9205-6228","position":10,"is_corresponding":false},{"id":344132,"name":"Vincent M. Tutino","orcid":"0000-0002-1331-2551","position":11,"is_corresponding":false},{"id":808990,"name":"Pinaki Sarder","orcid":"0000-0003-2450-5233","position":12,"is_corresponding":false},{"id":281043,"name":"Moshe Levi","orcid":"0000-0001-6403-2261","position":13,"is_corresponding":false},{"id":997409,"name":"Koji Okamoto","orcid":"0000-0001-7587-0164","position":14,"is_corresponding":false},{"id":33037,"name":"Cheryl A. Winkler","orcid":"0000-0001-5552-0917","position":15,"is_corresponding":false},{"id":225761,"name":"Jeffrey B. Kopp","orcid":"0000-0001-9052-186X","position":16,"is_corresponding":false},{"id":318523,"name":"Teruhiko Yoshida","orcid":"0000-0002-2049-7347","position":0,"is_corresponding":true}],"reference_count":62,"raw_metadata":null,"created_at":"2026-07-19T01:20:12.316631Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}