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 suggested an elevated urinary quinolinate/tryptophan ratio (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 a dose-related increase in circulating NAD⁺ metabolites. NAM was well tolerated and was associated with less AKI. Therefore, impaired NAD⁺ biosynthesis may be a feature of high-risk hospitalizations for which NAD⁺ augmentation could be beneficial.

中文翻译：

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从头开始的NAD +生物合成损伤在人类急性肾损伤中的作用。

烟酰胺腺嘌呤二核苷酸（NAD ⁺）延长了实验生物的寿命，引起了人们对其对人类健康的影响的兴趣。色氨酸的从头NAD ⁺生物合成在进化上是保守的，但考虑到烟酰胺（NAM）的生物合成已取代了高等物种。在这里，我们显示了从头开始生物合成中的瓶颈酶，喹啉酸磷酸核糖基转移酶（QPRT），捍卫肾脏NAD ⁺并介导对急性肾脏损伤（AKI）的抵抗力。鼠AKI后，肾脏NAD ⁺下降，喹啉酸上升，QPRT下降。QPRT ^+/-小鼠表现出更高的喹啉酸盐，更低的NAD ⁺以及更高的AKI敏感性。代谢组学提示尿喹啉/色氨酸比值（uQ / T）升高是降低QPRT的指标。uQ / T升高可预测危重患者的AKI和其他不良后果。口服NAM的1期安慰剂对照研究表明，循环NAD ⁺代谢产物的剂量相关增加。NAM具有良好的耐受性，并且与AKI减少有关。因此，NAD ⁺生物合成受损可能是高危住院的一个特征，NAD ⁺增强可能会有益于高危住​​院。