Abstract: PO1666
Protein Kinase R Inhibition Ameliorates Mitochondrial Dysfunction in the Tg26 HIV-Associated Nephropathy Mouse Model
Session Information
- Podocyte Injury in Human Disease: Pathomechanism, Diagnosis, and Therapy
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1202 Glomerular Diseases: Immunology and Inflammation
Authors
- Yoshida, Teruhiko, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
- Latt, Khun Zaw, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
- Rosenberg, Avi Z., Johns Hopkins University, Baltimore, Maryland, United States
- Shrivastav, Shashi, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
- Heymann, Jurgen, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
- Levi, Moshe, Georgetown University, Washington, District of Columbia, United States
- Winkler, Cheryl Ann, Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States
- Kopp, Jeffrey B., National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
Background
Double-stranded RNA (dsRNA)-activated protein kinase (PKR) is a sensor for dsRNA in response to viral infections, including HIV-1. We previously reported that APOL1 risk alleles damage podocytes through double-stranded RNA-activated protein kinase (PKR) activation (Okamato, Comm Biol, 2018). Here, we hypothesized that PKR activation could be a mechanistic pathway shared by HIV- and APOL1-mediated nephropathies. Hence, we investigated the effects of PKR inhibition on HIVAN in the well-characterized Tg26 mouse model, which expresses HIV regulatory and accessory genes.
Methods
We evaluated the kidney phenotype of Tg26 mice and wild-type mice treated with the PKR inhibitor (C16) from 6 to 12 weeks of age. We profiled kidney gene expression by RNA-seq and mitochondrial function by the extracellular flux assay using ex vivo glomerular tissues.
Results
Kidney disease manifestations, including albuminuria (mean [IQR]) (668 mg/g Cr [60, 1064] vs 2564 [1785, 5646], p=0.03) and global glomerulosclerosis (0.0% [0.0-0.0] vs 8.1 [2.3, 15.8], p=0.008),were reduced in the C16 treated group compared to the vehicle control group. C16 treatment increased mitochondrial gene expression (Fig.A), ameliorated mitochondrial dysfunction, and restored spare respiratory capacity as measured by extracellular flux assay (Fig.B).
Conclusion
PKR inhibition ameliorated mitochondrial dysfunction associated with the HIVAN phenotype observed in Tg26 mice, suggesting that PKR activation contributes to the development of mitochondrial dysfunction in HIVAN.
Funding
- NIDDK Support