Increased renal endothelin‐1 (ET‐1) production and an ETA receptor‐dependent increase in glomerular albumin permeability (Palb) accompany type 1 diabetes mellitus (T1D). We hypothesized that T1D‐induced oxidative stress contributes to renal ET‐1 production and glomerular Palb. Male rats with streptozotocin‐induced T1D were provided free access to drinking water without additives (T1D rats) or containing the free radical scavenger tempol (1 mmol/L; T1D+Tempol). After 3 weeks, T1D+Tempol rats displayed lower urinary excretion of thiobarbituric acid reactive substances and glomerular superoxide production (dihydroethidium staining) compared to T1D rats. Urinary ET‐1 excretion and inner medullary (but not cortical or outer medullary) prepro‐ET‐1 mRNA expression were lower in the T1D+Tempol group than in the T1D group. Palb, measured as the change in volume of isolated glomeruli upon exposure to oncotic gradients of albumin, was significantly lower in the T1D+Tempol group than in the T1D group. Tempol treatment did not alter protein excretion or creatinine clearance. These data support the postulate that oxidative stress contributes to glomerular Palb and renal ET‐1 production during the early phase of type 1 diabetes.
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.
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