Diabetes · 2016 · 124 citations · 33 references
MedicineNephrologyPharmacologyCell SignalingDiabetologyRenal PathophysiologyCellular Responses To HypoxiaChronic Kidney DiseaseDiabetic Kidney DiseaseDiabetic NephropathyRenal DiseaseRenal FibrosisHif-1 SignalingHypoxia-induced FibrosisHypoxia-inducible Factor SignalingMesangial ExpansionNadph Oxidase ActivityRenal Fibrosis MechanismsRenal Hypoxia SignalingRenal Responses To Hypoxia
Hypoxia-inducible factor (HIF)-1 mediates hypoxia- and chronic kidney disease-induced fibrotic events. Here, we assessed whether HIF-1 blockade attenuates the manifestations of diabetic nephropathy in a type 1 diabetic animal model, OVE26. YC-1 [3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole], an HIF-1 inhibitor, reduced whole kidney glomerular hypertrophy, mesangial matrix expansion, extracellular matrix accumulation, and urinary albumin excretion as well as NOX4 protein expression and NADPH-dependent reactive oxygen species production, while blood glucose levels remained unchanged. The role of NOX oxidases in HIF-1-mediated extracellular matrix accumulation was explored in vitro using glomerular mesangial cells. Through a series of genetic silencing and adenoviral overexpression studies, we have defined GLUT1 as a critical downstream target of HIF-1α mediating high glucose-induced matrix expression through the NADPH oxidase isoform, NOX4. Together, our data suggest that pharmacological inhibition of HIF-1 may improve clinical manifestations of diabetic nephropathy.
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Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage
Takeshi Nishikawa, Diane Edelstein, Xue Du et al. · Nature · 2000 · 4.3K citations