Metabolomics reveals signature of mitochondrial dysfunction in diabetic kidney
Authors Sharma K, Karl B, Mathew AV, Gangoiti JA, Wassel CL, Saito R, Pu M, Sharma S,
You YH, Wang L, Diamond-Stanic M, Lindenmeyer MT, Forsblom C, Wu W, Ix JH,
Ideker T, Kopp JB, Nigam SK, Cohen CD, Groop PH, Barshop BA, Natarajan L, Nyhan
WL, Naviaux RK
Submitted By Submitted Externally on 2/7/2014
Status Published
Journal Journal of the American Society of Nephrology : JASN
Year 2013
Date Published 11/1/2013
Volume : Pages 24 : 1901 - 1912
PubMed Reference 23949796
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 PGC1a (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.

Investigators with authorship
Kumar SharmaUniversity of California San Diego