Cell stress response impairs de novo NAD+ biosynthesis in the kidney
Yohan Bignon, Anna Rinaldi, Zahia Nadour, Virginie Poindessous, Ivan Nemazanyy, Olivia Lenoir, Baptiste Fohlen, Pierre Weill-Raynal, Alexandre Hertig, Alexandre Karras, Pierre Galichon, Maarten Naesens, Dany Anglicheau, Pietro E. Cippà, Nicolas Pallet
Yohan Bignon, Anna Rinaldi, Zahia Nadour, Virginie Poindessous, Ivan Nemazanyy, Olivia Lenoir, Baptiste Fohlen, Pierre Weill-Raynal, Alexandre Hertig, Alexandre Karras, Pierre Galichon, Maarten Naesens, Dany Anglicheau, Pietro E. Cippà, Nicolas Pallet
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Research Article Metabolism Nephrology

Cell stress response impairs de novo NAD+ biosynthesis in the kidney

Abstract

The biosynthetic routes leading to de novo nicotinamide adenine dinucleotide (NAD+) production are involved in acute kidney injury (AKI), with a critical role for quinolinate phosphoribosyl transferase (QPRT), a bottleneck enzyme of de novo NAD+ biosynthesis. The molecular mechanisms determining reduced QPRT in AKI, and the role of impaired NAD+ biosynthesis in the progression to chronic kidney disease (CKD), are unknown. We demonstrate that a high urinary quinolinate-to-tryptophan ratio, an indirect indicator of impaired QPRT activity and reduced de novo NAD+ biosynthesis in the kidney, is a clinically applicable early marker of AKI after cardiac surgery and is predictive of progression to CKD in kidney transplant recipients. We also provide evidence that the endoplasmic reticulum (ER) stress response may impair de novo NAD+ biosynthesis by repressing QPRT transcription. In conclusion, NAD+ biosynthesis impairment is an early event in AKI embedded with the ER stress response, and persistent reduction of QPRT expression is associated with AKI to CKD progression. This finding may lead to identification of noninvasive metabolic biomarkers of kidney injury with prognostic and therapeutic implications.

Authors

Yohan Bignon, Anna Rinaldi, Zahia Nadour, Virginie Poindessous, Ivan Nemazanyy, Olivia Lenoir, Baptiste Fohlen, Pierre Weill-Raynal, Alexandre Hertig, Alexandre Karras, Pierre Galichon, Maarten Naesens, Dany Anglicheau, Pietro E. Cippà, Nicolas Pallet

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Figure 1

Impaired NAD+ biosynthesis is a very early event in AKI.

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Impaired NAD+ biosynthesis is a very early event in AKI. (A) Distributio...
(A) Distribution of quinolinate/tryptophan (uQ/T) levels measured in urine at baseline, and the day after cardiopulmonary bypass (CPB), according to the occurrence of AKI during the week after CPB. (B) Correlation between uQ/T levels measured in urine the day after CPB and the rate of variation in serum creatinine between the baseline and the maximum value in the week after CPB. P value was computed with Student’s t test. (C) Volcano plot comparing urinary metabolites of 41 patients collected 24 hours after CPB and who eventually developed AKI the week after surgery. (D) Receiver operating characteristic curves for the association between the concentrations of urinary tissue inhibitor of metalloproteinases-2 (TIMP-2) multiplied by insulin-like growth factor-binding protein 7 (IGFBP7), KIM-1, NGAL, retinol binding protein (RBP), and uQ/T collected the day after CPB and the occurrence of AKI the week after surgery. P values were computed with χ2 test, n = 41. (E) Increase of uQ/T levels between the day after CPB and baseline as a function of increase of urinary QPRT transcripts levels between the day after CPB and baseline. P value was computed with Student’s t test. (F) Expression of QPRT measured by RNA sequencing (RNA-Seq) of mRNA isolated from whole-kidney biopsies in a cohort of 42 KTRs before implantation (PRE) and shortly after the restoration of the blood flow (POST). P value was computed with Student’s t test. (G) Decrease of QPRT transcript levels as a function of the increase in HAVCR1 transcript levels measured by RNA-Seq of mRNA isolated from whole-kidney biopsies in a cohort of 42 KTRs shortly after the restoration of the blood flow (POST). P value was computed with Student’s t test. (H) Expression of Qprt transcripts measured by RNA-Seq of mRNA isolated from whole mouse kidneys examined at different time points following bilateral ischemia-reperfusion injury (IRI): (n = 3 to 4 mice per condition). P value was computed with 1-way ANOVA. RPKM, reads per kilobase per million mapped reads.