The Protective Effects Of Valsartan On Kidney In The Experimental Diabetic Rats

Background and objective Diabetic nephropathy (DN) is not only a common microvascular complications of diabetes mellitus but also the major cause of the end stage renal disease (ESRD). Theories concerning the pathogenesis of DN must explain its characteristic structural and functional changes, such as hypertfiltration, renal and glomerular hypertrophy, mesangial matrix accumulation, glomerular basement membrane thickening. Investigators have increasingly utilized animal models and cell culture to search for the factors responsible for these typical physiologic, structural and biochemical changes. Cytokines / growth factors have been identified as important factors in the pathogenesis of diabetic nephropathy, such as endothelin-1 (ET-l),nitric oxide (NO) and vascular endothelia growth factor (VEGF). ET-1 produces a dose-dependent systemic vasconstriction and increases in blood pressure. In addention to its systemic effects, in the kidney endothelin constricts glomerular mesangial cells and both the afferent and tne efferent arterioles, which might produce high glomerular capillary pressure. In addition , ET-1 might contribute to the proliferation of renal intrinsic cells and synthesis of extracellular matrix (ECM) ,which suggests ET-1 might play an important role in glomerular sclerosis. There were many effects of NO on kidney , such as dilatating artery , inhibiting adherence and aggregation of thrombocyte, increasing blood-supply of renal tissue , inhibiting cellular proliferation and accumulation of mesangial protein and increasing the vascular permeability. Abnormalities in endothelial function, such as increased endothelial permeability to macromolecules and endothelial proliferation,may be involved in the pathogenesis of diabetic microvascular complications. But the exact mechanisms remain incompletely defined. VEGF is an attractive candidate in this regard because VEGF markedly increases vascular permeability to macromolecules , potently stimulates the vascular endothelial cell to divide and tissue factor production.Angiotensin II (Ang II) plays an important role in the pathogenesis of DN. Ang II could be blocked by Angiotensin II receptor blocker(ARB) at receptor level which has the effect of renal protection. But the definite mechanisms remain elusive.In the present study local ET-1, NO, and VEGF in the kidney tissue were measured at the different stages of streptozotocin(STZ)-induced DN to investigate their effects in the pathogenesis of DN. Meanwhile Valsartan was used in the DN rat model to explore the mechanisms of its renal protective effects on DN by observing its influence on ET-1 > NO and VEGF.Methods 48 normal male Wistar rats were divided into two groups at random. After 10 hours fast the rats in one group (n=32) were performed peritoneal injection of 50mg/Kg STZ and the rats in the other group (n=16) were performed injection of sham citrate buffer with the equal volume. 72 hours later, the rat whose blood glucose level was above 16.7mmol/L and urine glucose was positive(+++-++++) was identified as diabetic rat. The rat whose blood glucose was less than 16.7mmol/L and urine glucose was negative was identified as normal. The 32 diabetic rats were subdivided into two groups equally at random. There were three groups totally in present study: Group I : n=16, normal rats, equal volume N.S. was perfused into stomach everyday. Group II: n=16, diabetic rats, same volume N.S. was perfused into stomach everyday. Group III: n=16, diabetic rats, 24mg/Kg valsartan was perfused into stomach everyday. In each group 6 rats were killed two weeks later and the other 10 were killed 12 weeks later. During the period of the experiment, free food and water without insuline or oral hypoglycemic agent were given to these rats. Just before the rats were killed, the quantity of 24hr urinary protein, the body weight, creatinine clearance rate were measured. After the rats were killed the kidneys wereremoved and weighted. The level of ET-1 in renal cortex tissue was evaluated by radio-immuni...