Metabolomics Reveals Signature of Mitochondrial Dysfunction ... : Journal of the American Society of Nephrology (original) (raw)

Clinical Research

Metabolomics Reveals Signature of Mitochondrial Dysfunction in Diabetic Kidney Disease

Sharma, Kumar*,†,‡,§; Karl, Bethany*,†,§; Mathew, Anna V.†,§; Gangoiti, Jon A.‖; Wassel, Christina L.¶; Saito, Rintaro*,†,‡; Pu, Minya¶; Sharma, Shoba†; You, Young-Hyun*,†; Wang, Lin**; Diamond-Stanic, Maggie*,†,§; Lindenmeyer, Maja T.††; Forsblom, Carol‡‡; Wu, Wei§§; Ix, Joachim H.†,§; Ideker, Trey‡; Kopp, Jeffrey B.‖‖; Nigam, Sanjay K.§§; Cohen, Clemens D.††; Groop, Per-Henrik‡‡,¶¶; Barshop, Bruce A.*,‖; Natarajan, Loki*,¶; Nyhan, William L.*,‖; Naviaux, Robert K.*,‡,‖,**

*Institute of Metabolomic Medicine,

†Center for Renal Translational Medicine, Division of Nephrology-Hypertension,

‡Divison of Medical Genetics, Department of Medicine,

¶Department of Family and Preventive Medicine, and

§§Departments of Pediatrics, Medicine and Cell and Molecular Medicine, University of California San Diego, San Diego, California;

§Division of Nephrology-Hypertension, Veterans Affairs San Diego Healthcare System, San Diego, California;

‖Biochemical Genetics Program, Division of Genetics, Department of Pediatrics, and

**Mitochondrial and Metabolic Disease Center, Departments of Medicine, Pediatrics, and Pathology, University of California San Diego, La Jolla, California;

††Division of Nephrology, University Hospital Zurich, Switzerland;

‡‡Folkhälsan Institute of Genetics, Folkhälsan Research Center and Division of Nephrology, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland;

‖‖Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Bethesda, Maryland; and

¶¶IDI Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia

Correspondence: Dr. Kumar Sharma, Institute of Metabolomic Medicine, Center for Renal Translational Medicine, Division of Nephrology-Hypertension, 405 Stein Clinical Research Building, MC 0711, University of California San Diego, La Jolla, CA 92093.Email: [email protected]

Received February 01, 2013

Accepted June 11, 2013

Abstract

Diabetic kidney disease is the leading cause of ESRD, but few biomarkers of diabetic kidney disease are available. This study used gas chromatography-mass spectrometry to quantify 94 urine metabolites in screening and validation cohorts of patients with diabetes mellitus (DM) and CKD(DM+CKD), in patients with DM without CKD (DM–CKD), and in healthy controls. Compared with levels in healthy controls, 13 metabolites were significantly reduced in the DM+CKD cohorts (_P_≤0.001), and 12 of the 13 remained significant when compared with the DM–CKD cohort. Many of the differentially expressed metabolites were water-soluble organic anions. Notably, organic anion transporter-1 (OAT1) knockout mice expressed a similar pattern of reduced levels of urinary organic acids, and human kidney tissue from patients with diabetic nephropathy demonstrated lower gene expression of OAT1 and OAT3. Analysis of bioinformatics data indicated that 12 of the 13 differentially expressed metabolites are linked to mitochondrial metabolism and suggested global suppression of mitochondrial activity in diabetic kidney disease. Supporting this analysis, human diabetic kidney sections expressed less mitochondrial protein, urine exosomes from patients with diabetes and CKD had less mitochondrial DNA, and kidney tissues from patients with diabetic kidney disease had lower gene expression of PGC1α (a master regulator of mitochondrial biogenesis). We conclude that urine metabolomics is a reliable source for biomarkers of diabetic complications, and our data suggest that renal organic ion transport and mitochondrial function are dysregulated in diabetic kidney disease.