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. IntroductionThe most striking abnormalities of the renin-Ang system (RAS) in the blood of diabetic animals are the decreased renin level and the increased prorenin level (1). Indeed, increased blood prorenin levels in human diabetics have been reported to predict microvascular complications (2). Recent studies have demonstrated that transgenic rats expressing prorenin have severe renal histopathology mimicking diabetic nephrosclerosis without hypertension (3) and show evidence that circulating prorenin may enter organs (4). The mechanism whereby intracellular prorenin causes organ damage remained unclear, however.Prorenin has a prosegment of 43 amino acid residues attached to the N terminus of mature (active) renin, and the prosegment folds into an active site cleft of mature renin to prevent catalytically productive interaction with angiotensinogen. When a proreninbinding protein interacts with the "handle" region of the prorenin prosegment, the prorenin molecule undergoes a conformational change to an enzymatically active state (5). This phenomenon is called nonproteolytic activation, and such binding proteins include a specific Ab to the prosegment (5), the N-acyl-D-glucos-

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.

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Although lowering blood pressure (BP) reduces aortic stiffness, achieving the recommended BP goal can be difficult. Recent studies have shown that short-term use of statins can reduce BP significantly. To determine the long-term effects of statins on BP and aortic stiffness, a single-blind randomized prospective study was performed on 85 hyperlipidaemic hypertensive patients whose BP was insufficiently controlled by antihypertensive therapy. Every 3 months, aortic stiffness was assessed by measuring pulse wave velocity (PWV). Patients were randomly allocated to groups treated with pravastatin, simvastatin, fluvastatin, or a nonstatin antihyperlipidaemic drug. No significant differences in patient characteristics, kinds of antihypertensive drugs, BP, ankle brachial index, PWV, or serum lipid, creatinine, or C-reactive protein levels were found between the four groups at the start of the study. During the 12-month treatment period, PWV did not change in the pravastatin group or nonstatin group, but it was transiently reduced in the simvastatin group and significantly decreased in the fluvastatin group, even though the doses of the statins used in this study were lower than the usually prescribed dose. All four antihyperlipidaemic drugs significantly decreased serum cholesterol levels without affecting BP, ankle brachial index, or serum triglyceride levels. The Creactive protein serum levels decreased significantly in the three statin groups but not in the nonstatin group. These results suggest that long-term use of fluvastatin by hyperlipidaemic hypertensive patients is associated with a significant reduction in aortic stiffness without any effect on BP.

Abstract. For determining the effects of anandamide (ANA) on renal hemodynamics and microcirculation, a clearance study was performed in Sprague-Dawley rats that received injections of ANA in doses of 15, 150, and 1500 pmol/kg. At doses up to 150 pmol/g, ANA significantly decreased GFR and increased renal blood flow (RBF) without affecting mean arterial pressure (MAP). In the presence of the cannabinoid type 1 (CB1) receptor antagonist AM251, only the 15-pmol/kg dose significantly increased GFR and RBF without altering MAP, with higher doses having no effect on GFR, RBF, or MAP. By contrast, AM281, which antagonizes cannabinoid receptors nonselectively, inhibited the GFR, RBF, and MAP responses to ANA. The arteriolar responses to ANA were also assessed in vitro by the blood-perfused juxtamedullary nephron technique.Higher doses of ANA significantly increased the diameter of both afferent and efferent arterioles, whereas lower doses elicited predominant efferent arteriolar dilation. AM251 attenuated the afferent arteriolar response to ANA and inhibited the efferent arteriolar response to ANA, whereas AM281 inhibited the responses in both arterioles. The CB1 receptor mRNA was expressed in afferent arterioles, and immunohistochemical staining demonstrated the presence of CB1 receptors in both afferent and efferent arterioles. These results suggest that ANA causes afferent arteriolar dilation via both CB1 and non-CB1 receptors and greater efferent arteriolar dilation via CB1 receptors, resulting in a decreased GFR and an increased RBF without affecting MAP.Septic shock is principally characterized by severe hemodynamic changes, including hypotension, decreased systemic vascular resistance, and compromised renal function. Although systemic hypotension seems to be involved in the decrease in GFR, some studies have demonstrated that decreased GFR during the early stage of sepsis is independent of systemic hemodynamics (1). Accordingly, some factors generated during sepsis may contribute to the compromised renal function independent of systemic hypotension.Endogenous cannabinoid levels increase during lipopolysaccharide-induced septic shock and cause systemic hypotension through the cannabinoid type 1 (CB1) receptors (2). A recent study suggested that the polymyxin B-immobilized beads column used clinically to treat endotoxic shock may abolish the hypotensive, immunosuppressive, and cytotoxic effects during endotoxin shock by adsorbing anandamide (ANA), an endogenous cannabinoid generated by activated macrophages (3).Moreover, molecular studies have confirmed the intrarenal presence of an ANA signaling system that includes ANA, its putative precursor, the enzyme catalyzing the breakdown of ANA, and CB1 receptors (4 -6). However, no studies of the direct effect of ANA on renal function have ever been reported.The present study was designed to assess the direct effect of exogenous ANA on renal hemodynamics. Periglomerular microcirculatory responses to ANA were also assessed by using an in vitro blood-perfused juxtamedulla...