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.
Highlights
Nicotinamide adenine dinucleotide (NAD+) is a cofactor involved in oxidation-reduction reactions and serves as an energy transfer intermediate in multiple metabolic pathways [1]
Urinary quinolinate phosphoribosyltransferase (QPRT) transcripts were negatively correlated with urinary quinolate/tryptophan ratio (uQ/T) levels, in line with the fact that elevated uQ/T is an indirect marker of reduced QPRT activity (Figure 1E)
QPRT mRNA levels were significantly reduced in the first hours after ischemia-reperfusion injury (IRI) in protocol biopsies obtained in 42 kidney transplant recipients (KTRs) before and after reperfusion [12] (Figure 1F)
Summary
Nicotinamide adenine dinucleotide (NAD+) is a cofactor involved in oxidation-reduction reactions and serves as an energy transfer intermediate in multiple metabolic pathways [1]. Recent experimental and clinical data demonstrated a critical role for NAD+ homeostasis in acute kidney injury (AKI) [4,5,6,7]. Proximal tubular cells (PTCs) are highly metabolically active, and their survival and function depend on the ability to couple their energetic needs to the regulation of energy generation, antioxidant responses, and mitochondrial biogenesis and quality control, all of which rely on cytosolic and mitochondrial NAD+ [5, 8]. Reduction in QPRT activity during AKI is considered critical in NAD+ biosynthetic impairment [6], but the molecular mechanisms determining reduced QPRT upon kidney injury and its role in long-term outcomes after AKI remain unclear. The clinical relevance of noninvasive monitoring of QPRT activity in patients with kidney disease is not established
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
