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Nicotinamide adenine dinucleotide (NAD.sup.+) extends longevity in experimental organisms, raising interest in its impact on human health. De novo NAD.sup.+ 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.sup.+ and mediates resistance to acute kidney injury (AKI). Following murine AKI, renal NAD.sup.+ fell, quinolinate rose, and QPRT declined. QPRT.sup.+/- mice exhibited higher quinolinate, lower NAD.sup.+, 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.sup.+ metabolites. NAM was well tolerated and was associated with less AKI. Therefore, impaired NAD.sup.+ biosynthesis may be a feature of high-risk hospitalizations for which NAD.sup.+ augmentation could be beneficial. Impaired NAD.sup.+ biosynthesis may be a common feature of high-risk hospitalizations for which NAD.sup.+ augmentation could improve therapeutic outcome., Author(s): Ali Poyan Mehr [sup.1] , Mei T. Tran [sup.1] , Kenneth M. Ralto [sup.1] [sup.2] [sup.3] , David E. Leaf [sup.4] , Vaughan Washco [sup.1] , Joseph Messmer [sup.1] [...]

PGC1[alpha] protects against kidney injury by upregulating enzymes that enhance nicotinamide adenine dinucleotide (NAD) and driving local accumulation of the fatty acid breakdown product [beta]-hydroxybutyrate, which leads to increased production of the renoprotective prostaglandin E.sub.2. Kidney protection by PGC1[alpha] Samir Parikh and colleagues show that the mitochondrial biogenesis regulator PGC1[alpha] protects against kidney injury by regulating NAD biosynthesis. In a mouse model, PGC1[alpha] upregulates NAMPT, an enzyme required form for NAD.sup.+ biosynthesis, and drives local accumulation of the fatty acid breakdown product [beta]-hydroxybutyrate. This, in turn, leads to increased production of the renoprotective prostaglandin PGE.sub.2. The authors further show that treatment with the NAD precursor nicotinamide (NAM) can reverse established ischaemic kidney injury. The energetic burden of continuously concentrating solutes against gradients along the tubule may render the kidney especially vulnerable to ischaemia. Acute kidney injury (AKI) affects 3% of all hospitalized patients.sup.1,2. Here we show that the mitochondrial biogenesis regulator, PGC1[alpha].sup.3,4, is a pivotal determinant of renal recovery from injury by regulating nicotinamide adenine dinucleotide (NAD) biosynthesis. Following renal ischaemia, Pgc1[alpha].sup.-/- (also known as Ppargc1a.sup.-/-) mice develop local deficiency of the NAD precursor niacinamide (NAM, also known as nicotinamide), marked fat accumulation, and failure to re-establish normal function. Notably, exogenous NAM improves local NAD levels, fat accumulation, and renal function in post-ischaemic Pgc1[alpha].sup.-/- mice. Inducible tubular transgenic mice (iNephPGC1[alpha]) recapitulate the effects of NAM supplementation, including more local NAD and less fat accumulation with better renal function after ischaemia. PGC1[alpha] coordinately upregulates the enzymes that synthesize NAD de novo from amino acids whereas PGC1[alpha] deficiency or AKI attenuates the de novo pathway. NAM enhances NAD via the enzyme NAMPT and augments production of the fat breakdown product [beta]-hydroxybutyrate, leading to increased production of prostaglandin PGE.sub.2 (ref. 5), a secreted autacoid that maintains renal function. NAM treatment reverses established ischaemic AKI and also prevented AKI in an unrelated toxic model. Inhibition of [beta]-hydroxybutyrate signalling or prostaglandin production similarly abolishes PGC1[alpha]-dependent renoprotection. Given the importance of mitochondrial health in ageing and the function of metabolically active organs, the results implicate NAM and NAD as key effectors for achieving PGC1[alpha]-dependent stress resistance., Author(s): Mei T. Tran [sup.1] [sup.2] , Zsuzsanna K. Zsengeller [sup.1] [sup.2] [sup.3] , Anders H. Berg [sup.3] [sup.4] , Eliyahu V. Khankin [sup.1] [sup.2] , Manoj K. Bhasin [sup.2] [...]

Acute kidney injury (AKI) arising from diverse etiologies is characterized by mitochondrial dysfunction. The peroxisome proliferator-activated receptor γ coactivator-1alpha (PGC1α), a master regulator of mitochondrial biogenesis, has been shown to be protective in AKI. Interestingly, reduction of PGC1α has also been implicated in the development of diabetic kidney disease and renal fibrosis. The beneficial renal effects of PGC1α make it a prime target for therapeutics aimed at ameliorating AKI, forms of chronic kidney disease (CKD), and their intersection. This review summarizes the current literature on the relationship between renal health and PGC1α and proposes areas of future interest. [ABSTRACT FROM AUTHOR]