Ovariectomy enhances renal cortical expression and function of cyclooxygenase-2

Ovariectomy enhances renal cortical expression and function of cyclooxygenase-2.BackgroundCyclooxygenase-2 (COX-2) inhibitors are used as analgesics in postmenopausal women, who develop edema and require a salt-restricted diet. This study was performed to determine the renal expression of COX-2 and on COX-2–dependent regulation of renal blood flow (RBF) in ovariectomized rats.MethodsSprague-Dawley rats were divided into 4 groups: sham-operated rats fed a normal-salt diet (Sh+NS) or a low-salt diet (Sh+LS), and bilaterally ovariectomized rats fed a normal-salt diet (Ox+NS) or a low-salt diet (Ox+LS) (N = 6 in each group). Estrogen replacement therapy was performed on other ovariectomized rats. A renal clearance study was performed in anesthetized animals.ResultsOvariectomy increased renal cortical COX-2 expression independently of dietary salt intake (Sh+NS <Ox+N; Sh+LS <Ox+LS). Inhibition of COX-2 by NS398 reduced the urinary excretion of 6-keto-prostaglandin F1α in all 4 groups, although the reduction was greater in the Ox+LS group than in the Ox+NS and Sh+LS groups, which in turn had a greater reduction than the Sh+NS group. RBF significantly decreased in every group except the Sh+NS group, but no effect on blood pressure, inulin clearance, or urinary sodium excretion was seen. The decrease in RBF was significantly greater in the Ox+LS group than in the Sh+LS and Ox+NS group. The decrease in RBF was dependent on cortical RBF in the Sh+LS and Ox+NS groups, and on both cortical and medullary RBF in the Ox+LS group. Estrogen replacement therapy reversed the ovariectomy-induced changes.ConclusionEstrogen-dependent COX-2 expression plays an important role in the RBF regulation in female rats

Inhibition of diabetic nephropathy by a decoy peptide corresponding to the “handle” region for nonproteolytic activation of prorenin

We found that when a site-specific binding protein interacts with the “handle” region of the prorenin prosegment, the prorenin molecule undergoes a conformational change to its enzymatically active state. This nonproteolytic activation is completely blocked by a decoy peptide with the handle region structure, which competitively binds to such a binding protein. Given increased plasma prorenin in diabetes, we examined the hypothesis that the nonproteolytic activation of prorenin plays a significant role in diabetic organ damage. Streptozotocin-induced diabetic rats were treated with subcutaneous administration of handle region peptide. Metabolic and renal histological changes and the renin-Ang system components in the plasma and kidneys were determined at 8, 16, and 24 weeks following streptozotocin treatment. Kidneys of diabetic rats contained increased Ang I and II without any changes in renin, Ang-converting enzyme, or angiotensinogen synthesis. Treatment with the handle region peptide decreased the renal content of Ang I and II, however, and completely inhibited the development of diabetic nephropathy without affecting hyperglycemia. We propose that the nonproteolytic activation of prorenin may be a significant mechanism of diabetic nephropathy. The mechanism and substances causing nonproteolytic activation of prorenin may serve as important therapeutic targets for the prevention of diabetic organ damage