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Abstract: PO1820

Protein Kinase R Inhibition Ameliorates Tg26 HIV-Associated Nephropathy Mouse Model

Session Information

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
  • Okamoto, Koji, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, 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
  • Kopp, Jeffrey B., National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
Background

HIV-associated nephropathy (HIVAN) has become less common with widespread use of antiretroviral therapy but has not yet disappeared. Double-stranded RNA (dsRNA)-activated protein kinase (PKR) is a sensor for dsRNA in response to viral infection such caused by HIV. We previously reported that APOL1 risk alleles damages podocytes through double-stranded RNA-activated protein kinase (PKR) activation. Thus, we hypothesized that PKR activation could be an activated pathway shared in the pathology of HIV- and APOL1-mediated nephropathies. We tested this hypothesis by investigating whether PKR inhibition would ameliorate HIVAN using the well-established Tg26 mouse model.

Methods

We evaluated the kidney phenotype of Tg26 mice and wild type mice treated with or without the PKR inhibitor (C16) from 6 to 12 weeks of age. We quantified albuminuria after treatment and evaluated kidney pathology after 6-week treatment.

Results

We confirmed the activation of PKR in Tg26 mice kidney by Western blot. We saw a significant decrease in kidney disease development in the PKR inhibitor (C16) treatment group compared to the vehicle control group. Urine albumin/creatinine ratio (mg/gCr; mean [IQR]) was 668 [60-1064] in the treatment Tg26 group and 2564 [1786-5646) in the vehicle control Tg26 group (P=0.026). Kidney pathology showed fewer sclerotic glomeruli and tubular microcystic lesions in the treated Tg26 group than in the vehicle control Tg26 group.

Conclusion

PKR inhibition ameliorated HIVAN phenotype of Tg26 mouse, suggesting that PKR activation contributes to the pathophysiology of HIVAN in this model.

Fig: Urine albumin/creatinine ratio after treatment

Funding

  • NIDDK Support