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

HIV 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 Stat3 as a potential mediating factor. We identified in Tg26 mice a novel proximal tubular cell cluster enriched in mitochondrial transcripts. Podocytes showed high HIV-1 gene expression and dysregulation of cytoskeleton-related genes and these cells dedifferentiated and were lost. Cell-cell interaction analysis suggested that the profibrogenic PKR-STAT3-PDGF-D pathway was activated in injured proximal tubules and was triggered by PDGFRB-expressing fibroblasts throughout the cortex. These findings suggest that PKR inhibition and mitochondrial rescue as potential novel therapeutic approaches for HIVAN. Translational Statement This work highlighted mitochondrial dysfunction in HIV-associated nephropathy mice kidney by combination of single-nuclear and bulk RNA-seq analysis. We ameliorated the kidney damage by PKR inhibitor C16 treatment showing mitochondrial rescue by transcriptomic profiling and functional assay. This transcriptomic-driven characterization showed that PKR inhibition and mitochondrial rescue as potential therapeutic approaches for HIV-associated nephropathy.