Metabolomics reveals signature of mitochondrial dysfunction in diabetic kidney disease.
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.
Institute of Metabolomic Medicine.
Kumar
K
Sharma
Bethany
B
Karl
Anna V
AV
Mathew
Jon A
JA
Gangoiti
Christina L
CL
Wassel
Rintaro
R
Saito
Minya
M
Pu
Shoba
S
Sharma
Young-Hyun
YH
You
Lin
L
Wang
Maggie
M
Diamond-Stanic
Maja T
MT
Lindenmeyer
Carol
C
Forsblom
Wei
W
Wu
Joachim H
JH
Ix
Trey
T
Ideker
Jeffrey B
JB
Kopp
Sanjay K
SK
Nigam
Clemens D
CD
Cohen
Per-Henrik
PH
Groop
Bruce A
BA
Barshop
Loki
L
Natarajan
William L
WL
Nyhan
Robert K
RK
Naviaux
D000328:Adult; D000368:Aged; D003928:Diabetic Nephropathies / Q000378:metabolism*; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D017136:Ion Transport; D008297:Male; D055432:Metabolomics / Q000379:methods*; D008875:Middle Aged; D028361:Mitochondrial Diseases / Q000209:etiology*; D027362:Organic Anion Transport Protein 1 / Q000235:genetics; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D051436:Renal Insufficiency, Chronic / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics
D027362:Organic Anion Transport Protein 1; D029362:Organic Anion Transporters, Sodium-Independent; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors; C114338:organic anion transport protein 3