Diabetic nephropathy: a disorder of oxygen metabolism?

Abstract

Chronic hypoxia induces sequential abnormalities in oxygen metabolism (for example, oxidative stress, nitrosative stress, advanced glycation, carbonyl stress, endoplasmic reticulum stress) in the kidneys of individuals with diabetes. Identification of these abnormalities improves our understanding of therapeutic benefits that can be achieved with antihypertensive agents, the control of hyperglycemia and/or hyperinsulinemia and the dietary correction of obesity. Key to the body's defense against hypoxia is hypoxia-inducible factor, the activity of which is modulated by prolyl hydroxylases (PHDs)-oxygen sensors whose inhibition may prove therapeutic. Renal benefits of small-molecule PHD inhibitors have been documented in several animal models, including those of diabetic nephropathy. Three different PHD isoforms have been identified (PHD1, PHD2 and PHD3) and their respective roles have been delineated in knockout mouse studies. Unfortunately, none of the current inhibitors is specific for a distinct PHD isoform. Nonspecific inhibition of PHDs might induce adverse effects, such as those associated with PHD2 inhibition. Specific disruption of PHD1 induces hypoxic tolerance, without angiogenesis and erythrocytosis, through the reprogramming of basal oxygen metabolism and decreased generation of oxidative stress in hypoxic mitochondria. A specific PHD1 inhibitor might, therefore, offer a novel therapy for abnormal oxygen metabolism not only in the diabetic kidney, but also in other diseases for which hypoxia is a final, common pathway.

myo-Inositol Oxygenase Overexpression Accentuates Generation of Reactive Oxygen Species and Exacerbates Cellular Injury following High Glucose Ambience

“…5). The fact that NOX4 siRNA treatment partially blocked the generation of ROS would also suggest that ROS are derived from dual sources in MIOX-overexpressing cells under high glucose ambience, as has been described in various investigations related to diabetic nephropathy in various animal models (1,3,9,10,50).…”

“…E, MIOX activity; at basal levels (LG), it was designated as 100%, and a relative percentage increase in various samples was calculated. A dosedependent increase in enzyme activity was observed with various concentrations of D-glucose but not with L-glucose or transfection of EV (E, columns [1][2][3][4][5]. However, MIOX-pcDNA transfection led to a ϳ2-fold increase in enzyme activity even at LG concentration, whereas it increased by another 50% under HG ambience, and it was normalized to almost basal levels with MIOX siRNA treatment (E, columns 6, 7, and 9).…”

The proximal tubule in the pathophysiology of the diabetic kidney

“…Abnormalities in oxygen metabolism have been implicated in the development and progression of diabetic nephropathy and include hypoxia, oxidative stress, nitrosative stress, and advanced glycation and/or carbonyl stress (44,71,93). A role of hypoxia in chronic renal disease was proposed by Fine et al (39) and has been confirmed in human and animal models, including the diabetic kidney (96,134).…”

Oxygen regulation of the epithelial Na channel in the collecting duct

“…There has been considerable discussion about how renal hypoxia may contribute to progression of renal disease (18,39). However, it is well recognized that obesity can predispose to salt-sensitive hypertension well before there is evidence of kidney disease.…”