2. Academic Validation
  3. NAD deficiency contributes to progressive kidney disease in HIV nephropathy mice

NAD deficiency contributes to progressive kidney disease in HIV nephropathy mice

  • Am J Physiol Renal Physiol. 2024 Jul 4. doi: 10.1152/ajprenal.00061.2024.
Teruhiko Yoshida 1,  Komuraiah Myakala 2,  Bryce A Jones 2,  Xiaoxin X Wang 2,  Shashi Shrivastav 3,  Briana A Santo 4,  Tatsat R Patel 5,  Yongmei Zhao 6,  Vincent M Tutino 7,  Pinaki Sarder 8,  Avi Z Rosenberg 9,  Cheryl A Winkler 10,  Moshe Levi 11,  Jeffrey B Kopp 12
Affiliations

Affiliations

  • 1 Kidney Disease Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, United States.
  • 2 Biochemistry and Molecular & Cellular Biology, Georgetown University, WASHINGTON, DC, United States.
  • 3 National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States.
  • 4 Pathology and Anatomical Sciences, University at Buffalo, State University of New York, Buffalo, NY, United States.
  • 5 Department of Pathology and Anatomical Sciences, University at Buffalo, State University of New York, Buffalo, NY, United States.
  • 6 Bioinformatics and Computational Science, Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States.
  • 7 Department of Pathology and Anatomical Sciences, University at Buffalo, State University of New York, Buffalo, United States.
  • 8 University at Buffalo, United States.
  • 9 Department of Pathology, Johns Hopkins Medicine, Baltimore, MD, United States.
  • 10 Basic research Laboratory, Center for Cancer Research, Frederick National Laboratory for Cancer Research, Frederick, MD, United States.
  • 11 Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Washington, DC, United States.
  • 12 National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, United States.
PMID: 38961841 DOI: 10.1152/ajprenal.00061.2024
Abstract

HIV disease remains prevalent in the USA and is particularly prevalent in sub-Saharan Africa. Recent investigations revealed that mitochondrial dysfunction in kidney contributes to HIV-associated nephropathy (HIVAN) in Tg26 transgenic mice. We hypothesized that nicotinamide adenine dinucleotide (NAD) deficiency contributes to energetic dysfunction and progressive tubular injury. We investigated metabolomic mechanisms of HIVAN tubulopathy. Tg26 and wild-type (WT) mice were treated with the farnesoid-X receptor (FXR) agonist INT-747 or nicotinamide riboside (NR) from 6 to 12 weeks of age. Multi-omic approaches were used to characterize kidney tissue transcriptomes and metabolomes. Treatment with INT-747 or NR ameliorated kidney tubular injury, as shown by serum creatinine, the tubular injury marker urinary neutrophil-associated lipocalin and tubular morphometry. Integrated analysis of metabolomic and transcriptomic measurements showed that NAD levels and production were globally downregulated in Tg26 mouse kidney, especially nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting Enzyme in the NAD salvage pathway. Further, NAD-dependent deacetylase sirtuin3 activity and mitochondrial Oxidative Phosphorylation activity were lower in ex vivo proximal tubules from Tg26 mouse kidneys compared to those of WT mice. Restoration of NAD levels in kidney improved these abnormalities. These data suggest that NAD deficiency might be a treatable target for HIVAN.

Keywords

HIV; NAD; RNA-seq; metabolomics; mitochondria.

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