Abstract: SA-PO1043
Nicotinamide Adenine Dinucleotide (NAD) Deficiency Contributes to Progressive Kidney Disease in HIV Nephropathy Mice
Session Information
- Pathology and Lab Medicine - II
November 04, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Pathology and Lab Medicine
- 1800 Pathology and Lab Medicine
Authors
- Yoshida, Teruhiko, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
- Myakala, Komuraiah, Georgetown University, Washington, District of Columbia, United States
- Jones, Bryce A., Georgetown University, Washington, District of Columbia, United States
- Wang, Xiaoxin, Georgetown University, Washington, District of Columbia, United States
- Shrivastav, Shashi, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
- Santo, Briana A., University at Buffalo, Buffalo, New York, United States
- Zhao, Yongmei, Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States
- Tutino, Vincent M., University at Buffalo, Buffalo, New York, United States
- Sarder, Pinaki, University of Florida, Gainesville, Florida, United States
- Rosenberg, Avi Z., Johns Hopkins University, Baltimore, Maryland, United States
- Levi, Moshe, Georgetown University, Washington, District of Columbia, United States
- Kopp, Jeffrey B., National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
Background
HIV disease remains prevalent in the USA and is even more highly prevalent in sub-Saharan Africa. Recent investigations revealed that renal mitochondrial dysfunction 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.
Methods
Tg26 and wild-type (WT) mice were treated with nicotinamide riboside (NR), 500 mg/kg body weight/day in drinking water or the farnesoid-X receptor agonist INT-747, 10 mg/kg body weight/day in the diet from 6 to 12 weeks of age. We used multi-omic characterization of kidney tissue transcriptomes and metabolomes to investigate metabolomic mechanisms of HIVAN tubulopathy and the effects of treatment with NR and INT-747.
Results
Treatment with NR and INT-747 ameliorated kidney tubular injury in Tg26 mice, as shown by serum creatinine, urine albumin and the tubular injury marker, urinary neutrophil-associated lipocalin (NGAL). NAD levels were significantly lower (2.86 [2.54-3.28, IQR] nmol/mg) in Tg26 kidney compared with WT mouse kidney (6.94 [5.48-8.72] nmol/mg) and levels were restored by either NR or INT-747 treatment. Integrated analysis of transcriptomic and metabolomic measurements showed that the NAD salvage pathway was downregulated in Tg26 mouse kidney. Sirtuin3 acetylation activity and mitochondrial oxidative phosphorylation activity were lower in ex vivo proximal tubules from Tg26 kidneys compared to those of WT mice. These activities were restored by supplementation with NR and with INT-747.
Conclusion
NAD deficiency contributes to HIVAN tubulopathy and mitochondrial dysfunction in Tg26 mice. Restoration of NAD levels in kidney improves these pathologies.
(A-D) Representative PAS staining images of mouse kidney, (E) NAD signaling pathway map overlaying transcriptomic and metabolomic results comparing Tg26 and WT mice.
Funding
- NIDDK Support