Mitochondrial Dysfunction and PKR Activation in HIV-Associated Nephropathy in Transgenic Mice

Core Concepts

Mitochondrial dysfunction is a central mechanism for proximal tubule injury in the Tg26 HIVAN mouse model, and this process is largely reversed by treatment with the PKR inhibitor C16.

Abstract

The study used a combination of bulk RNA-sequencing and single-nucleus RNA-sequencing to investigate the molecular mechanisms underlying HIV-associated nephropathy (HIVAN) in the Tg26 transgenic mouse model. The key findings are: PKR inhibition by the compound C16 ameliorated the kidney phenotype in Tg26 mice, including reduced albuminuria, glomerulosclerosis, and interstitial fibrosis. Bulk RNA-seq and single-nucleus RNA-seq analyses revealed that the oxidative phosphorylation pathway was one of the most downregulated pathways in Tg26 mice, suggesting mitochondrial dysfunction as a central mechanism. This mitochondrial dysfunction was rescued by PKR inhibition. A novel proximal tubular cell cluster (PT-Mito) with high mitochondrial gene expression was identified, and this cluster showed pronounced mitochondrial dysfunction in Tg26 mice. Podocytes in Tg26 mice exhibited high expression of HIV-1 genes, especially nef and vpr, and showed dedifferentiation and dysregulation of cytoskeleton-related pathways. Cell-cell interaction analysis identified a potential fibrogenic pathway involving the PKR-STAT3-PDGF-D axis in injured proximal tubules of Tg26 mice, which was ameliorated by PKR inhibition. In summary, this study highlights the central role of mitochondrial dysfunction and PKR activation in the pathogenesis of HIVAN, and suggests that PKR inhibition and mitochondrial rescue may be potential therapeutic approaches.

Stats

Tg26 mice had lower serum creatinine compared to control Tg26 mice after C16 treatment. Tg26 mice had reduced albuminuria after C16 treatment compared to control Tg26 mice. C16 treatment reduced urinary excretion of the kidney injury marker NGAL in Tg26 mice. C16 treatment reduced glomerulosclerosis and interstitial fibrosis in Tg26 mice. Mitochondrial gene expression was downregulated in Tg26 mice compared to wild-type, and this was rescued by C16 treatment. Mitochondrial respiratory capacity was reduced in glomeruli and proximal tubules of Tg26 mice, and this was restored by C16 treatment.

Quotes

"PKR inhibition by the PKR-specific oxoindole/imidazole inhibitor C16 might rescue kidney injury in Tg26 mice." "Mitochondrial dysfunction in Tg26 mouse glomeruli and myocytes has been previously reported." "Podocytes showed the highest levels of transgene expression, which is consistent with the prominent pathology observed in podocytes."

Key Insights Distilled From

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

by Yoshida,T., ... at www.biorxiv.org 10-07-2022

https://www.biorxiv.org/content/10.1101/2022.10.03.510678v4

Deeper Inquiries

How do the findings from this mouse model translate to the pathogenesis of HIVAN in human patients?

The findings from this mouse model provide valuable insights into the pathogenesis of HIV-associated nephropathy (HIVAN) in human patients. The identification of mitochondrial dysfunction as a central mechanism in the development of kidney injury in the Tg26 HIVAN mouse model is significant. Mitochondrial dysfunction has been implicated in various kidney diseases, including HIVAN in humans. The dysregulation of mitochondrial genes, as observed in the mouse model, may reflect similar processes occurring in human HIVAN patients. Additionally, the activation of the PKR-STAT3 pathway and the downstream effects on fibrogenic pathways, as seen in the mouse model, could also be relevant to the pathogenesis of HIVAN in humans. These findings suggest that targeting mitochondrial dysfunction and the PKR-STAT3 pathway may hold promise as therapeutic strategies for HIVAN in human patients.

What other signaling pathways or cellular processes, besides mitochondrial dysfunction and PKR activation, may contribute to the development of HIVAN?

In addition to mitochondrial dysfunction and PKR activation, several other signaling pathways and cellular processes may contribute to the development of HIV-associated nephropathy (HIVAN). One important pathway is the renin-angiotensin system (RAS), which plays a crucial role in regulating blood pressure and fluid balance in the kidneys. Dysregulation of the RAS has been implicated in the pathogenesis of various kidney diseases, including HIVAN. Inflammatory pathways, such as the NF-kB pathway, may also play a role in the development of HIVAN by promoting inflammation and tissue damage in the kidneys. Moreover, dysregulation of the Notch signaling pathway has been linked to kidney fibrosis and injury in HIVAN. Additionally, pathways involved in oxidative stress, apoptosis, and cell adhesion may contribute to the pathogenesis of HIVAN by promoting cellular damage and dysfunction in the kidneys.

Could the novel PT-Mito cell cluster identified in this study serve as a potential therapeutic target or biomarker for HIVAN?

The novel proximal tubular cell cluster enriched in mitochondrial transcripts, known as PT-Mito, identified in this study could potentially serve as a valuable therapeutic target or biomarker for HIV-associated nephropathy (HIVAN). The high expression levels of mitochondrial genes in this cluster suggest that these cells may play a critical role in the pathogenesis of HIVAN, particularly in the context of mitochondrial dysfunction. Targeting the PT-Mito cluster specifically with therapeutic interventions aimed at restoring mitochondrial function or reducing cellular stress could potentially mitigate kidney injury in HIVAN. Additionally, the PT-Mito cluster could serve as a biomarker for assessing the severity of mitochondrial dysfunction and kidney injury in HIVAN patients. By monitoring the expression levels of mitochondrial genes in this cluster, clinicians could potentially track disease progression and response to treatment in HIVAN patients. Further research is needed to explore the therapeutic potential and diagnostic utility of the PT-Mito cell cluster in the context of HIVAN.