
HIV-1 遺伝子発現によって引き起こされるミトコンドリア機能障害と PKR 経路の活性化が、Tg26マウスにおける腎障害の主要な機序である。


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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 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.

Translational Statement This work identified mitochondrial dysfunction in transgenic mice manifesting HIV-associated nephropathy mice kidney, using combination of single-nuclear and bulk RNA-seq analysis. Kidney damage was ameliorated by the PKR inhibitor C16, and mitochondrial rescue was shown by transcriptomic profiling and functional assay. These findings suggest that PKR inhibition and mitochondrial rescue are potential therapeutic approaches for HIV-associated nephropathy.

### Competing Interest Statement

The authors have declared no competing interest.

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

hiv-1-遺伝子発現による腎障害の機序-tg26マウスにおけるミトコンドリア機能障害と-pkr-経路の活性化


HIV-1 遺伝子発現による腎障害の機序：Tg26マウスにおけるミトコンドリア機能障害と PKR 経路の活性化
