NAD Deficiency: a Treatable Target for HIV-Associated Nephropathy
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Introduction
Nicotinamide adenine dinucleotide (NAD) deficiency has been linked to a range of renal disorders, encompassing conditions such as acute kidney injury, diabetic nephropathy, adenine-triggered kidney disease, and focal segmental glomerulosclerosis caused by adriamycin. On this basis, a recent study further uncovers that NAD deficiency might be a treatable target for human immunodeficiency virus (HIV)-associated nephropathy (HIVAN).About HIVAN
HIVAN is a specific type of renal disease caused by HIV infection, which is clinically characterized by large amounts of proteinuria and rapid short-term decline in renal function. HIVAN exhibits renal pathological damage of collapsing focal segmental glomerulosclerosis, accompanied with the proliferation/hypertrophy/fusion of podocytes as well as severe tubulointerstitial inflammation and microcystic dilatation of the renal tubules. It is the leading cause of end-stage renal failure in HIV-infected patients.Research protocol
Wild-type (WT) and Tg26 HIV mice (age: 6-12 weeks) are subjected to the treatment of INT-747 (10 mg/kg body weight/day; diet), a synthetic ligand for the farnesoid X-receptor, or the treatment of nicotinamide riboside (NR; 500 mg/kg body weight/day; drinking water), an NAD+ precursor. Herein, 24-hour urine is collected using metabolic cages. Before and after treatment, the mouse body weight is measured as well. At week 12, their plasma, serum and kidney samples are collected for analyses of transcriptomics, metabolomics and digital pathology, as well as the detection by extracellular flux analyzer.![](http://v4-upload.goalsites.com/898/1721122409_image-20240716173330-3.jpeg)
The effect of INT-747 and NR on Tg26 mouse kidneys
Following six-week treatment of INT-747 and NR, the kidney injury in Tg26 mice is greatly alleviated, as indicated by the downregulated serum creatinine and urinary NGAL levels. Besides, pathological symptoms such as the glomerular segmental scarring and global glomerulosclerosis in Tg26 mice are ameliorated by INT-747/NR.![](http://v4-upload.goalsites.com/898/1721122421_image-20240716173342-4.jpeg)
Meanwhile, there is a decreased trend towards metabolites and genes in the tricarboxylic acid (TCA) cycle and oxidative phosphorylation, complex IV activity, as well as the expression of mitochondrial genes and proteins in Tg26 mouse kidneys, which however are rescued by INT-747/NR. Importantly, SIRT3 de-activation in Tg26 HIVAN mouse kidneys, one of the downstream factors of NAD that compromise mitochondrial function, is reversed by INT-747/NR as well. These findings signify the restoration of NAD+ metabolism and mitochondrial function.
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Conclusion
A deficiency in NAD is potentially responsible for the advancement of renal disease in mice with HIVAN. Treatment using either INT-747 or NR can replenish NAD levels, leading to an enhancement in kidney function. Replenishing NAD+ level is expected to be novel way for the alleviation of HIVAN.Reference
Yoshida Teruhiko, Myakala Komuraiah, Bryce A Jones, et al. (2024). NAD deficiency contributes to progressive kidney disease in HIV nephropathy mice. American journal of physiology. Renal physiology. 10.1152/ajprenal.00061.2024.BONTAC NAD
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