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

Abstract

Aims/hypothesis. The renal medullary region is particularly vulnerable to reduced oxygen concentration because of its low blood perfusion and high basal oxygen consumption. This study investigated renal metabolic changes in relation to the previously observed decreased oxygen tension in streptozotocin-induced diabetic rats. Methods. Blood perfusion, oxygen tension and consumption, interstitial pH, and glycolytic and purinebased metabolites were determined in the renal cortex and the medulla of non-diabetic and diabetic animals by, respectively, laser Doppler flowmetry, oxygen and pH microelectrodes, and microdialysis. The importance of increased polyol pathway activity for the observed alterations was investigated by daily treatment with the aldose reductase inhibitor AL-1576 throughout the course of diabetes.Results. The diabetes-induced decrease in renal oxygen tension, due to augmented oxygen consumption, did not result in manifest hypoxia in either the cortical or the medullary region, as evaluated by microdialysis measurements of purine-based metabolites. The profound alterations in medullary oxygen metabolism were, however, associated with an increased lactate : pyruvate ratio and a concomitantly decreased pH. Notably, the renal medullary changes in oxygen tension, oxygen consumption, lactate : pyruvate ratio and pH were preventable by inhibition of aldose reductase. Conclusions/interpretation. Substantial metabolic changes were observed in the renal medulla in diabetic animals. These disturbances seemed to be mediated by increased polyol pathway activity and could be prevented by inhibition of aldose reductase.

Expression of NG,NG-Dimethylarginine Dimethylaminohydrolase and Protein Arginine N-Methyltransferase Isoforms in Diabetic Rat Kidney

“…As reported in our previous studies in this STZ-induced diabetic rat model at 4 weeks (31,(33)(34)(35)(36)(37)(38), rats with diabetes had a significant decrease in body weight, an increase in blood glucose to ϳ400 mg/dl, an increase in urinary volume, and an increase in creatinine clearance without changes in mean blood pressure measured under anesthesia (Table 1). These parameters were not changed significantly by 2 weeks of telmisartan administration in both control or diabetic rats (Table 1).…”

“…After 3 days, the induction of diabetes was confirmed by urinary glucose excretion. As in our prior studies (31,(33)(34)(35)(36)(37)(38) no attempt was made to treat the diabetes with insulin, since we wished to study the pathophysiology of insulinopenic diabetes.…”

“…After 2 weeks of treatment and 4 weeks of diabetes, 24-h urine and blood were collected and rats were killed. Rats were allowed free access to food to permit ongoing hyperglycemia and hyperfiltration (31,(33)(34)(35)(36)(37)(38). The animals were anesthetized with pentobarbital (50 mg/kg body wt), the abdominal aorta was cannulated, blood pressure was measured with a pressure transducer, and the kidneys were perfused retrogradely with ice-cold PBS.…”

“…Administration of an ACE inhibitor or an Ang II receptor blocker (ARB) to STZ-induced diabetic rats or patients with type 2 diabetes reduces markers of inflammation, oxidative stress, and albuminuria, independent of blood pressure or creatinine clearance (31,32). We used the STZ-induced model of diabetes, which we had characterized (31,(33)(34)(35)(36)(37) to explore the regulation of DDAH and PRMT expression by Ang II type 1 receptors (AT 1 -Rs) in diabetes.…”

High Glucose Blunts Vascular Endothelial Growth Factor Response to Hypoxia via the Oxidative Stress-Regulated Hypoxia-Inducible Factor/Hypoxia-Responsible Element Pathway

“…*P Ͻ 0.05 versus hypoxia group; # P Ͻ 0.05 versus hypoxia and high d-glucose group. ticated techniques such as blood oxygen level-dependent (BOLD) magnetic resonance imaging revealed hypoxia in diabetic kidneys (23,24). The increased renal VEGF expression might contribute to pathologic intrarenal alterations in diabetic kidneys such as increased kidney weight, increased GFR, glomerular hypertrophy, and increased urinary albumin excretion.…”