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De novo NAD+ biosynthetic impairment in acute kidney injury in humans

Nicotinamide adenine dinucleotide (NAD+) extends longevity in experimental organisms, raising interest in its impact on human health. De novo NAD+ biosynthesis from tryptophan is evolutionarily conserved yet considered supplanted among higher species by biosynthesis from nicotinamide (Nam). Here we...

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Autores principales: Mehr, Ali Poyan, Tran, Mei T., Ralto, Kenneth M., Leaf, David E., Washco, Vaughan, Messmer, Joseph, Lerner, Adam, Kher, Ajay, Kim, Steven H., Khoury, Charbel C., Herzig, Shoshana J., Trovato, Mary E., Simon-Tillaux, Noemie, Lynch, Matthew R., Thadhani, Ravi I., Clish, Clary B., Khabbaz, Kamal R., Rhee, Eugene P., Waikar, Sushrut S., Berg, Anders H., Parikh, Samir M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6129212/
https://www.ncbi.nlm.nih.gov/pubmed/30127395
http://dx.doi.org/10.1038/s41591-018-0138-z
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author Mehr, Ali Poyan
Tran, Mei T.
Ralto, Kenneth M.
Leaf, David E.
Washco, Vaughan
Messmer, Joseph
Lerner, Adam
Kher, Ajay
Kim, Steven H.
Khoury, Charbel C.
Herzig, Shoshana J.
Trovato, Mary E.
Simon-Tillaux, Noemie
Lynch, Matthew R.
Thadhani, Ravi I.
Clish, Clary B.
Khabbaz, Kamal R.
Rhee, Eugene P.
Waikar, Sushrut S.
Berg, Anders H.
Parikh, Samir M.
author_facet Mehr, Ali Poyan
Tran, Mei T.
Ralto, Kenneth M.
Leaf, David E.
Washco, Vaughan
Messmer, Joseph
Lerner, Adam
Kher, Ajay
Kim, Steven H.
Khoury, Charbel C.
Herzig, Shoshana J.
Trovato, Mary E.
Simon-Tillaux, Noemie
Lynch, Matthew R.
Thadhani, Ravi I.
Clish, Clary B.
Khabbaz, Kamal R.
Rhee, Eugene P.
Waikar, Sushrut S.
Berg, Anders H.
Parikh, Samir M.
author_sort Mehr, Ali Poyan
collection PubMed
description Nicotinamide adenine dinucleotide (NAD+) extends longevity in experimental organisms, raising interest in its impact on human health. De novo NAD+ biosynthesis from tryptophan is evolutionarily conserved yet considered supplanted among higher species by biosynthesis from nicotinamide (Nam). Here we show that a bottleneck enzyme in de novo biosynthesis, quinolinate phosphoribosyltransferase (QPRT), defends renal NAD+ and mediates resistance to acute kidney injury (AKI). Following murine AKI, renal NAD+ fell, quinolinate rose, and QPRT declined. QPRT(+/−) mice exhibited higher quinolinate, lower NAD+, and higher AKI susceptibility. Metabolomics proposed elevated urinary quinolinate/tryptophan (uQ:T) as an indicator of reduced QPRT. Elevated uQ:T predicted AKI and other adverse outcomes in critically ill patients. A Phase 1 placebo-controlled study of oral Nam demonstrated dose-related increase in circulating NAD+ metabolites. Nam was well-tolerated and was associated with less AKI. Impaired NAD+ biosynthesis may therefore be a feature of high-risk hospitalizations for which NAD+ augmentation could be beneficial.
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spelling pubmed-61292122019-02-20 De novo NAD+ biosynthetic impairment in acute kidney injury in humans Mehr, Ali Poyan Tran, Mei T. Ralto, Kenneth M. Leaf, David E. Washco, Vaughan Messmer, Joseph Lerner, Adam Kher, Ajay Kim, Steven H. Khoury, Charbel C. Herzig, Shoshana J. Trovato, Mary E. Simon-Tillaux, Noemie Lynch, Matthew R. Thadhani, Ravi I. Clish, Clary B. Khabbaz, Kamal R. Rhee, Eugene P. Waikar, Sushrut S. Berg, Anders H. Parikh, Samir M. Nat Med Article Nicotinamide adenine dinucleotide (NAD+) extends longevity in experimental organisms, raising interest in its impact on human health. De novo NAD+ biosynthesis from tryptophan is evolutionarily conserved yet considered supplanted among higher species by biosynthesis from nicotinamide (Nam). Here we show that a bottleneck enzyme in de novo biosynthesis, quinolinate phosphoribosyltransferase (QPRT), defends renal NAD+ and mediates resistance to acute kidney injury (AKI). Following murine AKI, renal NAD+ fell, quinolinate rose, and QPRT declined. QPRT(+/−) mice exhibited higher quinolinate, lower NAD+, and higher AKI susceptibility. Metabolomics proposed elevated urinary quinolinate/tryptophan (uQ:T) as an indicator of reduced QPRT. Elevated uQ:T predicted AKI and other adverse outcomes in critically ill patients. A Phase 1 placebo-controlled study of oral Nam demonstrated dose-related increase in circulating NAD+ metabolites. Nam was well-tolerated and was associated with less AKI. Impaired NAD+ biosynthesis may therefore be a feature of high-risk hospitalizations for which NAD+ augmentation could be beneficial. 2018-08-20 2018-09 /pmc/articles/PMC6129212/ /pubmed/30127395 http://dx.doi.org/10.1038/s41591-018-0138-z Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Mehr, Ali Poyan
Tran, Mei T.
Ralto, Kenneth M.
Leaf, David E.
Washco, Vaughan
Messmer, Joseph
Lerner, Adam
Kher, Ajay
Kim, Steven H.
Khoury, Charbel C.
Herzig, Shoshana J.
Trovato, Mary E.
Simon-Tillaux, Noemie
Lynch, Matthew R.
Thadhani, Ravi I.
Clish, Clary B.
Khabbaz, Kamal R.
Rhee, Eugene P.
Waikar, Sushrut S.
Berg, Anders H.
Parikh, Samir M.
De novo NAD+ biosynthetic impairment in acute kidney injury in humans
title De novo NAD+ biosynthetic impairment in acute kidney injury in humans
title_full De novo NAD+ biosynthetic impairment in acute kidney injury in humans
title_fullStr De novo NAD+ biosynthetic impairment in acute kidney injury in humans
title_full_unstemmed De novo NAD+ biosynthetic impairment in acute kidney injury in humans
title_short De novo NAD+ biosynthetic impairment in acute kidney injury in humans
title_sort de novo nad+ biosynthetic impairment in acute kidney injury in humans
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6129212/
https://www.ncbi.nlm.nih.gov/pubmed/30127395
http://dx.doi.org/10.1038/s41591-018-0138-z
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