title: PGC1α drives NAD biosynthesis linking oxidative metabolism to renal protection.
abstract: 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. Here we show that the mitochondrial biogenesis regulator, PGC1α, is a pivotal determinant of renal recovery from injury by regulating nicotinamide adenine dinucleotide (NAD) biosynthesis. Following renal ischaemia, Pgc1α(-/-) (also known as Ppargc1a(-/-)) 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 Pgc1α(-/-) mice. Inducible tubular transgenic mice (iNephPGC1α) recapitulate the effects of NAM supplementation, including more local NAD and less fat accumulation with better renal function after ischaemia. PGC1α coordinately upregulates the enzymes that synthesize NAD de novo from amino acids whereas PGC1α deficiency or AKI attenuates the de novo pathway. NAM enhances NAD via the enzyme NAMPT and augments production of the fat breakdown product β-hydroxybutyrate, leading to increased production of prostaglandin PGE2 (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 β-hydroxybutyrate signalling or prostaglandin production similarly abolishes PGC1α-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 PGC1α-dependent stress resistance.
authors.affiliation: Division of Nephrology and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.|Center for Vascular Biology Research, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Mei T
authors.initials: MT
authors.lastname: Tran
authors.affiliation: Division of Nephrology and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.|Center for Vascular Biology Research, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.|Division of Clinical Chemistry, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Zsuzsanna K
authors.initials: ZK
authors.lastname: Zsengeller
authors.affiliation: Division of Clinical Chemistry, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.|Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Anders H
authors.initials: AH
authors.lastname: Berg
authors.affiliation: Division of Nephrology and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.|Center for Vascular Biology Research, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Eliyahu V
authors.initials: EV
authors.lastname: Khankin
authors.affiliation: Center for Vascular Biology Research, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.|Bioinformatics and Systems Biology Core, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Manoj K
authors.initials: MK
authors.lastname: Bhasin
authors.affiliation: Nephrology and Endocrine Divisions, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Wondong
authors.initials: W
authors.lastname: Kim
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02139, USA.
authors.forename: Clary B
authors.initials: CB
authors.lastname: Clish
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Isaac E
authors.initials: IE
authors.lastname: Stillman
authors.affiliation: Division of Nephrology and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.|Center for Vascular Biology Research, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.|Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA.
authors.forename: S Ananth
authors.initials: SA
authors.lastname: Karumanchi
authors.affiliation: Nephrology and Endocrine Divisions, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02139, USA.
authors.forename: Eugene P
authors.initials: EP
authors.lastname: Rhee
authors.affiliation: Division of Nephrology and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.|Center for Vascular Biology Research, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Samir M
authors.initials: SM
authors.lastname: Parikh
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000378:metabolism; D058186:Acute Kidney Injury / Q000188:drug therapy / Q000378:metabolism*; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D015232:Dinoprostone / Q000096:biosynthesis / Q000378:metabolism; D006801:Humans; D007511:Ischemia / Q000188:drug therapy / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D009243:NAD / Q000096:biosynthesis*; D009536:Niacinamide / Q000172:deficiency / Q000494:pharmacology / Q000627:therapeutic use; D054409:Nicotinamide Phosphoribosyltransferase / Q000378:metabolism; D010084:Oxidation-Reduction; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D015398:Signal Transduction / Q000187:drug effects; D013312:Stress, Physiological; D014157:Transcription Factors / Q000172:deficiency / Q000378:metabolism*
chemical_list: D000596:Amino Acids; D016207:Cytokines; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D014157:Transcription Factors; D009243:NAD; D009536:Niacinamide; D054409:Nicotinamide Phosphoribosyltransferase; C495867:nicotinamide phosphoribosyltransferase, mouse; D015232:Dinoprostone; D020155:3-Hydroxybutyric Acid