Glucose stimulates O₂consumption, NOS, and Na/H exchange in diabetic rat proximal tubules

Abstract

Endothelial nitric oxide synthase (NOS) and neuronal NOS protein increased in proximal tubules of acidotic diabetic rats 3-5 wk after streptozotocin injection. NOS activity (citrulline production) was similar in nondiabetic and diabetic tubules incubated with low glucose (5 mM glucose + 20 mM mannitol); but after 30 min with high glucose (25 mM), Ca-sensitive citrulline production had increased 23% in diabetic tubules. Glucose concentration did not influence citrulline production in nondiabetic tubules. High glucose increased carboxy-2-phenyl-4,4,5,5,-tetramethylimidazoline 1-oxyl-3-oxide (cpt10)-scavenged NO sevenfold in a suspension of diabetic tubules but did not alter NO in nondiabetic tubules. Diabetes increased ouabain-sensitive 86Rb uptake (141 +/- 9 vs. 122 +/- 6 nmol x min(-1) x mg(-1)) and oligomycin-sensitive O2 consumption (QO2; 16.0 +/- 1.7 vs. 11.3 +/- 0.7 nmol x min(-1) x mg(-1)). Ethylisopropyl amiloride-inhibitable QO2 (6.5 +/- 0.6 vs. 2.4 +/- 0.3 nmol x min(-1) x mg(-1)) accounted for increased oligomycin-sensitive QO2 in diabetic tubules. N(G)-monomethyl-L-arginine methyl ester (L-NAME) inhibited most of the increase in 86Rb uptake and QO2 in diabetic tubules. L-NAME had little effect on nondiabetic tubules. Inhibition of QO2 by ethylisopropyl amiloride and L-NAME was only 5-8% additive. Uncontrolled diabetes for 3-5 wk increases NOS protein in proximal tubules and makes NOS activity sensitive to glucose concentration. Under these conditions, NO stimulates Na-K-ATPase and QO2 in proximal tubules.

Reactive oxygen species cause diabetes-induced decrease in renal oxygen tension

“…Renal cortical cells from diabetic rats had increased oxygen consumption consistent with previously published results [16,17]. In our study, we also measured oxygen consumption of cells from the outer medulla and noted that these had an even more pronounced increase in oxygen consumption.…”

“…This results in a distinct gradient in oxygen tension from the renal cortex to the medulla [14,15]. Previous studies have shown that renal proximal tubular cells from diabetic animals have an increased oxygen consumption [16,17], whereas little is known concerning oxygen consumption in renal medullary cells.…”

Polyol-pathway-dependent disturbances in renal medullary metabolism in experimental insulin-deficient diabetes mellitus in rats

“…A perhaps more plausible explanation is therefore that the in-creased glucose load to the proximal tubular cells enhances the flux through the Na + /glucose co-transporters [17]. As a result, Na + /K + -ATPase up-regulates and thus increases oxygen consumption [17,27]. This explanation is also supported by results showing that the ouabain-sensitive inhibition of oxygen consumption was increased in the medullary cells of the diabetic animals.…”

“…The exact mechanism for this effect remains to be determined. Enhanced expression of uncoupling protein-2 has been found to occur during chronic hyperglycaemia [27]. Diabetes is also generally associated with increased gluconeogenesis [28] and fatty acid metabolism [29].…”

Early Changes With Diabetes in Renal Medullary Hemodynamics as Evaluated by Fiberoptic Probes and BOLD Magnetic Resonance Imaging

“…This increased oxygen consumption was thought to be mainly related to high metabolic activity. 47 Palm et al 15 also demonstrated that oxygen consumption of renal medullary and cortical cells were higher in diabetic rats. The fact that oxygen consumption is increased in the diabetic kidney, predominantly in the medulla, because of an increase in metabolic activity is likely to contribute to the enhanced hypoxia seen in diabetes.…”