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Kidney Week

Abstract: PO0355

De Novo NAD+ Biosynthesis May Promote AKI Resistance

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Clark, Amanda J., Boston Children's Hospital, Boston, Massachusetts, United States
  • Parikh, Samir M., Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States
Background

Acute kidney injury (AKI) is a wide-spread, costly condition with no treatment. Renal energy metabolism impairment is a key feature of AKI. Nicotinamide adenine dinucleotide (NAD+) plays a critical role in maintaining ATP and regulating energy metabolism. It is produced from three pathways: dietary tryptophan, niacin, and NAD+ recycling. Ischemic AKI suppresses de novo NAD+ biosynthesis from tryptophan, including the bottleneck enzyme, quinolinate phosphoribosyl transferase (QPRT). QPRT +/- mice have worse AKI after ischemia-reperfusion (IRI). It is unknown if these disturbances are specific to ischemia, whether QPRT suppression contributes to AKI, or if restoration of this minor NAD+ pathway may be sufficient to improve AKI.

Methods

Nephron-specific conditional QPRT over-expressing mice were created (Pax8-rtTA, tetO-QPRT, iNephQPRT). Cisplatin was administered to induce AKI. Parallel AKI was induced in QPRT +/- and QPRT +/+ mice. QPRT expression was measured via qPCR. AKI severity was assessed with serum biochemistries and histology.

Results

Toxic AKI suppressed QPRT mRNA proportionally to AKI severity (Fig C,D). QPRT +/- mice were more susceptible to toxic AKI (Fig A). Conversely, iNephQPRT mice exhibited protection against AKI (Fig B).

Conclusion

QPRT suppression is necessary for severe nephrotoxic injury, and renal tubular QPRT augmentation is sufficient to ameliorate injury. Given that de novo NAD+ synthesis is considered a minor contributor to steady-state NAD+ balance, these results provide striking evidence of this pathway’s importance to renal health during acute stress. Further, these findings implicate de novo NAD+ biosynthesis suppression as a pathogenic event in a mechanistically distinct context compared to IRI. Elucidating the regulation of QPRT and NAD+ homeostasis may be critical to understanding AKI physiology and developing novel therapies.

Funding

  • NIDDK Support