Metabolomics Reveals a Key Role for Fumarate in Mediating the Effects of NADPH
Oxidase 4 in Diabetic Kidney Disease.
Authors You YH, Quach T, Saito R, Pham J, Sharma K
Submitted By Kumar Sharma on 11/9/2015
Status Published
Journal Journal of the American Society of Nephrology : JASN
Year 2015
Date Published 7/1/2015
Volume : Pages Not Specified : Not Specified
PubMed Reference 26203118
Abstract The NADPH oxidase (NOX) isoform NOX4 has been linked with diabetic kidney
disease (DKD). However, a mechanistic understanding of the downstream effects of
NOX4 remains to be established. We report that podocyte-specific induction of
NOX4 in vivo was sufficient to recapitulate the characteristic glomerular
changes noted with DKD, including glomerular hypertrophy, mesangial matrix
accumulation, glomerular basement membrane thickening, albuminuria, and podocyte
dropout. Intervention with a NOX1/NOX4 inhibitor reduced albuminuria, glomerular
hypertrophy, and mesangial matrix accumulation in the F1 Akita model of DKD.
Metabolomic analyses from these mouse studies revealed that tricarboxylic acid
(TCA) cycle-related urinary metabolites were increased in DKD, but fumarate
levels were uniquely reduced by the NOX1/NOX4 inhibitor. Expression of fumarate
hydratase (FH), which regulates urine fumarate accumulation, was reduced in the
diabetic kidney (in mouse and human tissue), and administration of the NOX1/NOX4
inhibitor increased glomerular FH levels in diabetic mice. Induction of Nox4 in
vitro and in the podocyte-specific NOX4 transgenic mouse led to reduced FH
levels. In vitro, fumarate stimulated endoplasmic reticulum stress, matrix gene
expression, and expression of hypoxia-inducible factor-1a (HIF-1a) and TGF-ß.
Similar upregulation of renal HIF-1a and TGF-ß expression was observed in NOX4
transgenic mice and diabetic mice and was attenuated by NOX1/NOX4 inhibition in
diabetic mice. In conclusion, NOX4 is a major mediator of diabetes-associated
glomerular dysfunction through targeting of renal FH, which increases fumarate
levels. Fumarate is therefore a key link connecting metabolic pathways to DKD
pathogenesis, and measuring urinary fumarate levels may have application for
monitoring renal NOX4 activity.