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

Area of Science:

• Nephrology
• Virology
• Molecular Biology

Background:

• HIV-associated nephropathy (HIVAN) is a significant complication in HIV-1-positive patients.
• Host double-stranded RNA (dsRNA)-activated protein kinase (PKR) senses viral dsRNA, including HIV-1.
• Mitochondrial dysfunction is implicated in the pathogenesis of HIVAN.

Purpose of the Study:

• To investigate the therapeutic potential of PKR inhibition in HIVAN.
• To elucidate the molecular mechanisms underlying HIVAN, focusing on mitochondrial function and cellular pathways.
• To identify potential therapeutic targets for HIVAN.

Main Methods:

• Utilized the Tg26 transgenic mouse model of HIVAN.
• Administered compound C16 to inhibit PKR.
• Performed single-nucleus RNA-seq and bulk RNA-seq for transcriptomic analysis.
• Analyzed cell-cell interactions and identified cell clusters.

Main Results:

• PKR inhibition with compound C16 ameliorated the HIVAN kidney phenotype and reversed mitochondrial dysfunction.
• Oxidative phosphorylation was a significantly downregulated pathway in affected kidneys.
• Identified a novel proximal tubular cell cluster enriched in mitochondrial transcripts.
• Podocytes exhibited high HIV-1 gene expression and dedifferentiation.
• Activated the pro-fibrogenic PKR-STAT3-platelet-derived growth factor (PDGF)-D pathway in injured proximal tubules.

Conclusions:

• PKR inhibition is a promising therapeutic strategy for HIVAN.
• Mitochondrial rescue may be a key component in treating HIVAN.
• The PKR-STAT3-PDGF-D pathway is implicated in HIVAN pathogenesis.