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      Effect of Angiotensin II on Glomerular Structure in Streptozotocin-Induced Diabetic Rats

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          Background/Aims: The streptozotocin (STZ)-induced diabetic rat is a widely used animal model of human diabetic nephropathy. In this model, diabetic nephropathy progresses without significant elevation in blood pressure. Therefore, studies have examined the effect of hypertension in STZ spontaneously hypertensive rats (SHR). This study investigated angiotensin II (Ang II)-induced hypertension in diabetic nephropathy in the STZ-diabetic rat independent of deleterious genetic effects in SHR. Methods: Animals were divided as follows: nondiabetic controls (ND; n = 18); diabetic (STZ: 65 mg/kg; n = 16); Ang II-induced hypertensive ND (Ang II: 120 ng/kg/min; n = 9), and hypertensive diabetic rats (n = 18). Systolic blood pressure was measured by the tail-cuff method prior to STZ injection and then weekly. After 3 months, plasma creatinine, and 24-hour urine albumin and creatinine were measured and kidneys harvested for morphometry. Results: Ang II infusion increased systolic blood pressure in diabetic and ND rats. When combined with diabetes, Ang II increased albumin excretion rate (14-fold, p < 0.05), plasma creatinine (1.5-fold, p < 0.005) worsened creatinine clearance (37%, p < 0.002) and increased glomerular basement membrane width (1.2-fold, p < 0.0001). Conclusion: Ang II caused moderate hypertension and accelerated diabetic nephropathy and glomerular structural changes. The Ang II-infused STZ-diabetic rat is an excellent model to study the deleterious glomerular effects of hypertension on diabetes independent of genetic traits.

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          Most cited references 16

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          Angiotensin II stimulates extracellular matrix protein synthesis through induction of transforming growth factor-beta expression in rat glomerular mesangial cells.

          Angiotensin II (Ang II) has been implicated in the development of progressive glomerulosclerosis, but the precise mechanism of this effect remains unclear. In an experimental model, we have shown previously that TGF-beta plays a key role in glomerulosclerosis by stimulating extracellular matrix protein synthesis, increasing matrix protein receptors, and altering protease/protease-inhibitor balance, thereby inhibiting matrix degradation. We hypothesized that Ang II contributes to glomerulosclerosis through induction of TGF-beta. Ang II treatment of rat mesangial cells in culture increased TGF-beta and matrix components biglycan, fibronectin, and collagen type I at both the mRNA and protein levels in a time- and dose-dependent manner. Saralasin, a competitive inhibitor of Ang II, prevented the stimulation. Ang II also promoted conversion of latent TGF-beta to the biologically active form. Coincubation of mesangial cells with Ang II and neutralizing antibody to TGF-beta blocked the Ang II-induced increases in matrix protein expression. Continuous in vivo administration of Ang II to normal rats for 7 d resulted in 70% increases in glomerular mRNA for both TGF-beta and collagen type I. These results indicate that Ang II induces mesangial cell synthesis of matrix proteins and show that these effects are mediated by Ang II induction of TGF-beta expression. This mechanism may well contribute to glomerulosclerosis in vivo.
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            Interaction of metabolic and haemodynamic factors in mediating experimental diabetic nephropathy.

            Diabetic nephropathy seems to occur as a result of an interaction of metabolic and haemodynamic factors. Glucose dependent pathways are activated within the diabetic kidney. These include increased oxidative stress, renal polyol formation and accumulation of advanced glycated end-products. Haemodynamic factors are also implicated in the pathogenesis of diabetic nephropathy and include increased systemic and intraglomerular pressure and activation of various vasoactive hormone pathways including the renin-angiotensin system and endothelin. These haemodynamic pathways, independently and with metabolic pathways, activate intracellular second messengers such as protein kinase C and MAP kinase, nuclear transcription factors such as NF-kappaB and various growth factors such as the prosclerotic cytokine, TGF-beta and the angiogenic, permeability enhancing growth factor, VEGF. These pathways ultimately lead to increased renal albumin permeability and extracellular matrix accumulation which results in increasing proteinuria, glomerulosclerosis and tubulointerstitial fibrosis. Therapeutic strategies involved in the management and prevention of diabetic nephropathy include currently available treatments such as intensified glycaemic control and antihypertensive agents, particularly those which interrupt the renin-angiotensin system. More novel strategies to influence vasoactive hormone action or to inhibit various metabolic pathways such as inhibitors of advanced glycation, specific protein kinase C isoforms and aldose reductase are at present under experimental and clinical investigation. It is predicted that multiple therapies will be required to reduce the progression of diabetic nephropathy.
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              The early natural history of nephropathy in type 1 diabetes: II. Early renal structural changes in type 1 diabetes.

               Michael Mauer,  ,  K Drummond (2002)
              Renal structural abnormalities are known to precede the development of proteinuria, hypertension, and reduced renal function in patients with type 1 diabetes. The determinants of these early structural abnormalities are, however, largely unknown. The International Diabetic Nephropathy Study (IDNS) has recruited 243 children and adults (aged 10-40 years) in Montreal, Minneapolis, and Paris to identify and quantify these determinants. All study subjects were normotensive and had normal-to-high glomerular filtration rates (GFRs) and urinary albumin excretion rates (AERs) or =20 microg/min (microalbuminuria). Two renal biopsies are obtained at a 5-year intervals, with baseline and follow-up measures of renal function, blood pressure (BP), HbA(1c), plasma lipids, and AER. Herein, we examine the baseline renal biopsy morphometric findings in these subjects and in 87 kidney donor control subjects and explore the associations between findings and clinical and demographic variables. The principal morphometric abnormalities were increased glomerular basement membrane (GBM) width and fractional volume of mesangium [Vv(Mes/glom)] and mesangial matrix [Vv(MM/glom)]. The frequency of these abnormalities increased with increasing duration of diabetes but was observed as early as 2-8 years after onset. Diastolic BP (DBP), but not HbA(1c), was directly associated with these abnormalities. Elevated GFR was associated with only a small increase in peripheral glomerular capillary basement membrane filtration surface density. Center differences were detected in renal structural, renal functional, and BP parameters, especially between the Paris and North American centers. GBM width, Vv(Mes/glom), and Vv(MM/glom) are significantly increased even within a few years of onset of type 1 diabetes. These changes are detectable in normoalbuminuric patients and are related to duration, BP, and study site. Changes in these and other morphometric measures over 5-year follow-up should help clarify the roles of glycemia and other determinants of the rates of development of diabetic nephropathy lesions, as well as their relationships to early changes in BP, albumin excretion, and renal function.

                Author and article information

                Am J Nephrol
                American Journal of Nephrology
                S. Karger AG
                October 2004
                01 December 2004
                : 24
                : 5
                : 549-556
                aDepartment of Medicine, Divisions of Nephrology and Endocrinology, Diabetes, and Hypertension, bDepartment of Medicine, Division of Nephrology, and cDivision of Epidemiology, David Geffen School of Medicine at UCLA, LosAngeles, Calif., and dDepartment of Pediatrics, Division of Nephrology, University of Minnesota, Minneapolis, Minn., USA
                82001 Am J Nephrol 2004;24:549–556
                © 2004 S. Karger AG, Basel

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                Page count
                Figures: 3, Tables: 2, References: 28, Pages: 8
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                Original Report: Laboratory Investigation


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