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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] [...]