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 patients1,2. Here we show that the mitochondrial biogenesis regulator, PGC1α3,4, 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.

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Figure 1: NAM supplementation restores normal post-ischaemic response in Pgc1α−/− mice.
Figure 2: Metabolic protection in post-ischaemic iNephPGC1α mice.
Figure 3: NAM induces β-OHB downstream of PGC1α to augment PGE2.
Figure 4: PGC1α effectors, NAM as therapy, and PGC1α in human AKI.

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Acknowledgements

The authors thank B. Spiegelman (Harvard Medical School, Dana Farber Cancer Institute) for support from this project’s inception; M. Zeidel (Harvard Medical School, BIDMC) for advice; Z. Arany (University of Pennsylvania) for the VE-cadherin-tTA × TRE-PGC1α mice; A. Agarwal (University of Alabama, NIH P30-DK079337) for LC–MS measurements of serum creatinine; A. Kurmann and A. Hollenberg (Harvard Medical School, BIDMC) for thyroxine measurements; and P. Pacher (NIH) for cisplatin-treated kidneys for microscopy. This work was supported by R01-DK095072 and philanthropic funds to S.M.P.; K08-DK090142 and a grant from Satellite Healthcare to E.P.R.; and K08-DK101560 to E.V.K.

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Authors

Contributions

M.T.T. designed experiments, performed the breeding, genotyping, renal injury models, cellular studies, analysed data, and wrote the manuscript. Z.K.Z. and I.E.S. performed and analysed histopathology, enzyme histochemistry, electron microscopy, and the human biopsy immunohistochemistry studies. A.H.B. created LC–MS assays, measured metabolites for cellular experiments, and analysed metabolic results. E.V.K. and S.A.K. performed micro-ultrasounds and analysed flow results. M.K.B. analysed raw RNA sequencing data. W.K., C.B.C. and E.P.R. performed metabolomics, follow-up metabolite measurements, and in vivo experiments with cisplatin and NAM. S.M.P. designed the experiments, analysed results, and wrote the manuscript with input from all authors.

Corresponding author

Correspondence to Samir M. Parikh.

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The authors declare no competing financial interests.

Extended data figures and tables

Extended Data Figure 1 Regulation of PGC1α and other features of post-ischaemic kidneys.

a, Serum creatinine 24 h after sham or IRI (n = 5 versus 14 mice); ***P < 0.001. b, Absence of class-wide changes in intrarenal phospholipids 24 h after IRI versus sham operation (n = 6 per group; NS, not significant). Each bar represents one lipid species. P value calculated using two-way ANOVA. c, Renal PGC1α expression 24 h after sham or IRI (n = 5 animals per group); **P < 0.01. d, Correlation of LC–MS method for serum creatinine and serum cystatin C (measured by ELISA). e, Glomerular filtration rate in controls or 24 h after IRI was determined by two-phase exponential decay curves of fluorescently labelled inulin as described in Methods (n = 5 per group); *P < 0.05. f, Correlation of LC–MS method for serum creatinine with clearance of FITC–inulin. Curve fit according to formula sCr = κ/GFR where κ is a constant. Error bars, s.e.m.

Extended Data Figure 2 Exacerbation of fat accumulation and tubular injury in post-ischaemic Pgc1α−/− kidneys.

ad, Low- (top) and high- (bottom) power photomicrographs 24 h after IRI in wild-type (WT; a, c) versus Pgc1α−/− (KO; b, d) mice. Scale bars, 200 and 100 μm (top and bottom, respectively). e, f, Blinded scoring of tubular injury in cortex and outer stripe of outer medulla (OSOM) on 4-point injury scale as described in Methods (n = 8 wild-type versus 12 knockout mice); *P < 0.05. g, Di-/tri-acylglycerols (DAGs, TAGs) in renal homogenates of knockout mice at baseline and 24 h after injury (n = 6 per group). Each bar represents one lipid species. P value calculated using two-way ANOVA. Error bars, s.e.m.

Extended Data Figure 3 NAM reduction from IRI and PGC1α deficiency.

a, Heat maps (red, higher; green, lower) of Bonferroni-corrected significantly different metabolites in sham versus IRI kidneys and wild-type (WT) versus knockout (KO) kidneys. Metabolites listed in purple are shared between settings. b, Total ion chromatogram of polar, positive-ion mode method for representative wild-type IRI sample, with NAM peak at retention time of 3.88 min. Inset shows representative NAM peaks for kidney extracts from wild-type control (Ctrl) and wild-type IRI (IRI) mice. ce, Relative renal NAM abundance in kidneys of knockout mice versus wild-type littermates; wild-type littermates at baseline and 24 h after IRI; and knockout mice at baseline and 24 h after IRI (n = 6 per group). f, Relative renal NAM concentrations in kidneys of mice following vehicle (Veh) versus NAM treatment (400 mg kg−1 intraperitoneal for 4 days) with and without IRI 24 h before tissue collection (n = 6 per group). P values calculated with two-way ANOVA. g, h, Oil-Red-O stain (pink) for fat accumulation 24 h after IRI with or without NAM pre-treatment (400 mg kg−1 intraperitoneal for 4 days); scale bar, 20 μm. Error bars, s.e.m.; *P < 0.05, **P < 0.01, ***P < 0.001.

Extended Data Figure 4 Increased mitochondrial abundance and post-ischaemic protection in renal tubular epithelial transgenic mice (iNephPGC1α).

a, Schematic for generating iNephPGC1α mice. b, Relative renal PGC1α expression in control versus iNephPGC1α mice with and without 4 weeks of doxycycline in drinking water (n = 5 per group; **P < 0.01 versus all other groups). c, Ratio of kidney weight to total body weight (note body weights statistically indistinguishable as well, n = 4 per group). d, Example gross images with 1 cm scale of control versus iNephPGC1α kidney. e, Renal mitochondrial DNA (mtDNA) copy number as described in Methods. f, Relative renal gene expression of PGC1α targets (Ndufs1, Cycs, Atp5o), partnering transcription factors (Nrf1), and the mitochondrial transcription factor, Tfam. Results analysed by two-way ANOVA with P value for genotype as noted. n = 8 per group. *P < 0.05 versus control after Bonferroni correction. g, Western blot analysis of kidney lysates for transcription factor a, mitochondrial (TFAM)38 and loading control. h, i, Transmission electron microscopy of mitochondria sectioned perpendicular and parallel to long axis demonstrating normal morphology in iNephPGC1α mice (representative of n = 4 per group); scale bar, 500 nm. j, k, Blinded scoring of tubular injury in cortex and outer stripe of outer medulla (n = 8 control; 12 iNephPGC1α). Error bars s.e.m.; *P < 0.05, **P < 0.01; NS, not significant.

Extended Data Figure 5 Renal protection in systemic inflammation conferred by renal tubular epithelial, but not endothelial, PGC1α.

a, Serum creatinine 24 h after bacterial endotoxin injection (LPS O111:B4), n = 9 per group. b, Serum creatinine 24 h after bacterial endotoxin (LPS O111:B4) in endothelial-specific (VEC, VE-cadherin) PGC1α transgenic mice (VEC-tTA × TRE-PGC1α), n = 5 per group. Error bars, s.e.m., *P < 0.05; NS, not significant.

Extended Data Figure 6 PGC1α-dependent de novo NAD biosynthesis and NAD-dependent accumulation of β-OHB and PGE2.

a, Gene expression for de novo NAD biosynthetic pathway in control renal tubular cells versus 48 h after PGC1α knockdown (n = 3 per condition). The gene expression set corresponds to the eight transcripts whose abundance was measured in kidney homogenates in Fig. 3. P = 0.0001 by two-way ANOVA with Bonferroni-corrected comparisons as indicated. b, Correlation of renal NAM versus renal NAD in mice treated with vehicle or different doses of NAM (one intraperitoneal dose of 100–400 mg kg−1). Arbitrary units on x and y axes. c, Renal β-OHB concentrations in kidneys of mice following vehicle (Veh) versus NAM treatment (400 mg kg−1 intraperitoneal for 4 days) with and without IRI 24 h before tissue collection (n = 5 per group). P value calculated with two-way ANOVA. Dashed line indicates normal circulating concentration of β-OHB. d, Dosing for siRNA against HCAR2 in renal tubular cells. e, Dose–inhibition curve in renal tubular cells for PGE2 release following 24 h of mepenzolate bromide at the indicated concentrations (n = 3 replicates per concentration)33,34,35. f, g, Intracellular NAM and secreted β-OHB for renal tubular cells following treatment with NAM (1 μM for 24 h) with or without pre-treatment with the NAMPT inhibitor FK866 (10 nM, n = 6 per condition). h, PGE2 in conditioned media of renal tubular cells after control versus PGC1α knockdown and with and without exogenous β-OHB application (+, 5 mM, n = 6 per condition, P values versus control group). Error bars, s.e.m.; *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.

Extended Data Figure 7 Effects of PGC1α on renal metabolites and features of cisplatin nephrotoxicity.

ac, Relative renal NAD, β-OHB, and PGE2 concentrations in wild-type (WT) littermates versus Pgc1α−/− (KO) mice (n = 6 per group). d, Serum creatinine in genetic control mice for iNephPGC1α 24 h after IRI with vehicle versus mepenzolate (MPN, 10 mg kg−1 intraperitoneal) treatment (n = 5 per group). e, Serum creatinine in genetic control mice for iNephPGC1α 24 h after IRI with vehicle versus indomethacin (INDO, 10 mg kg−1 intraperitoneal) treatment (n = 6 per group). f, Transmission electron microscopy with cytochrome c oxidase enzyme histochemistry of proximal tubular cell 24 h following cisplatin exposure (25 mg kg−1 intraperitoneal) demonstrating mitochondrial injury. Scale bar, 500 nm. g, Relative renal NAM concentrations following cisplatin as in f. Error bars, s.e.m.; *P < 0.05, **P < 0.01, ***P < 0.001; NS, not significant.

Extended Data Figure 8 Renal immunostaining for PGC1α declines in human chronic kidney disease.

ad, Low- (a, b) and high- (c, d) power photomicrographs of PGC1α immunoreactivity (brown) in wild-type (WT, left) littermates and Pgc1α−/− (KO, right) kidneys. Scale bars, 100 and 50 μm. e, f, Representative results of peptide competition attenuating PGC1α immunoreactivity against human kidney (n = 4) as described in Methods. g, Representative immunostaining (brown) for PGC1α in a renal biopsy with chronic kidney disease (CKD). Scale bar, 50 μm. h, Results of scoring PGC1α immunostaining intensity (1, weakest; 4, strongest) in specimens with CKD by blinded operator. Each dot represents a unique specimen. Analysed with Mann–Whitney U-test.

Extended Data Figure 9 Evidence for renal-tubular-epithelial-PGC1α-dependent reversible vascular relaxation.

a, Serum creatinine in uninduced (−Dox) versus induced ( + Dox) iNephPGC1α mice (n = 8 mice per group). b, Comparison of serum creatinine with degree of renal PGC1α expression, P < 0.05. c, d, Serial serum creatinines in iNephPGC1α mice versus controls before PGC1α induction (OFF), after 4 weeks of PGC1α induction (ON), and after 4 weeks of washout (OFF), n = 5 per group; *P < 0.05 as calculated using repeated-measures ANOVA. eg, Comparison of serum creatinine at different time points with renal artery flow in iNephPGC1α mice from d, P < 0.05 when correlation coefficient r = −0.65. hj, Comparison of resistive index with renal artery flow volume in iNephPGC1α mice from d, P < 0.05 when correlation coefficient r = −0.80. k, Relative renal expression of VEGF and nitric oxide synthases 1 and 3 (n = 6 per group). Analysed by two-way ANOVA with Bonferroni corrections. l, Circulating thyroxine levels in iNephPGC1α mice with and without gene induction (n = 5 per group) to rule out Pax8-related thyrotoxicosis driving perfusion differences as previously described45. m, Relative renal expression for VEGF in Pgc1α−/− mice (KO) versus wild-type (WT) littermates (n = 6 per group). Error bars, s.e.m.; NS, not significant.

Extended Data Figure 10 Relative renal expression for NAMPT in wild-type (WT) mice before and 24 h after IRI (n = 6 per group).

Error bars, s.e.m.; NS, not significant.

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Tran, M., Zsengeller, Z., Berg, A. et al. PGC1α drives NAD biosynthesis linking oxidative metabolism to renal protection. Nature 531, 528–532 (2016). https://doi.org/10.1038/nature17184

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