Free Radical Scavenging Decreases Endothelin‐1 (ET‐1) Excretion and Glomerular Permeability During Diabetes

Abstract

Hyperglycemia induces renal oxidative stress and renal ET‐1 production. In the present study, we hypothesized that diabetes‐induced oxidative stress activates renal ET‐1 production and/or glomerular permeability. Hyperglycemia was induced in 250–275 g male Sprague‐Dawley rats by a single i.v. dose of streptozotocin (65 mg/kg). The free radical scavenger, tempol (1 mM), was provided to half of the hyperglycemic rats in the drinking water and the other half received vehicle. After 3 weeks, urine, plasma, and renal tissue were collected. Tempol treatment decreased urinary excretion of thiobarbituric acid reactive substances (3959 ± 329.1 nmol/day vs. 6706 ± 608.9 nmol/day, N=8, P<0.001), as well as ameliorated glomerular superoxide production as monitored by dihydroethidium staining. Tempol treatment diminished urinary ET‐1 excretion (16.4 ± 1.5 pg/day vs. 30.6 ± 2.6 pg/day, N=8, P<0.001). Inner medullary prepro‐ET‐1 was attenuated with tempol treatment (0.7±0.12 vs. 1.1±0.12, N=8, P<0.05), although tempol treatment did not change cortical or outer medullary preproET‐1 levels. Glomerular permeability, Palb, (change in glomerular volume induced by exposing isolated glomeruli to oncotic gradients of albumin) was attenuated with tempol treatment (0.42±0.17 vs. 0.80±0.04, N=4, P<0.05). Proteinuria and creatinine clearance were similar in both groups of rats. In conclusion, the free radical scavenger, tempol, attenuated the increase in renal oxidative stress, ET‐1 excretion, and glomerular permeability associated with the early phase of diabetes.