| Background： Diabetic nephropathy (DN) is the most important microvascularcomplications of diabetesmellitus(DM), atherosclerosis (AS) is the main pathologicalfeatures of diabetic macroangiopathy. In recent decades, with the development of cellbiology and molecular biology, the pathogenesis of DN has been extensive research andelaboration, but the exact mechanism remains unclear and lacks effective therapeuticmeasures in clinical practice, therefore, the pathogenesis and treatment of DN is stillthe focus of the present study.Urotensin II (U II) is considered to be the most powerful vasoconstrictor, and thecombination with its specific receptor14(GPR14) caused a series of biological effects.The study found that U-II in patients with DN were up-regulated, suggesting that U-IIsystem may play a role in the pathophysiology of DN. And previous studies confirmedthat U II is closely related to atherosclerosis.Objective：To investigate the role of UII/GPR14in kidney damage and the formation ofatherosclerosis in rats with diabetic nephropathy and its possible mechanisms.Mycophenolate mofetil (MMF) is a new immunosuppressive agents.In recent years, itseffect on reducing proteinuria and glomerular macrophage infiltration, inhibitingglomerular sclerosis, and its protective effect on the kidneys were discovered. but theresearch of MMF treatment for DN was not much. In this study of MMF treatment fordiabetic nephropathy in rats, observed changes with U-II/GPR14level in rats, toexplore the effect of MMF on the prevention and treatment of diabetic nephropathy andits possible mechanism,to provide the experimental basis for the prevention andtreatment of diabetic nephropathy.Methods：1. Establish animal models of type2diabetic nephropathy complicated byatherosclerosis: the model group was fed a high sugar and high fat diet. Six weekslater,model rats were given intraperitoneal injection of STZ40mg/kg.2. grouping: the17rats that successful modeling and survival were randomly divided into diabetic nephropathy (DN group8), given daily normal saline, and the MMF group(MZ group9), given MMF according to20mg kg-1d-1dose (soluble in1%sodiumcarboxymethyl cellulose) orally for10consecutive weeks. Both groups were fed ahigh sugar and high fat diet. Normal control group (NC group9), given daily normalsaline and basal diet. At the end of16weeks, all rats were killed, collecting specimens.3. Determine serum creatinine (Scr), blood urea nitrogen (BUN), glucose (GLU),cholesterol, triglycerides, high density lipoprotein, low density lipoprotein and24hurinary protein (24hU-TP); take the left kidney The specimens were weighed tocalculate the kidney weight index (kidney weight/body weight, KI).4.HE stained,light microscopy observation of aortic and renal pathological changes.5.Immunohistochemistry：observe the expression of UII/GPR14protein;detect theexpression of UIImRNA by RT-PCR.Results：1. Diabetic rats (DN and MZ group) register as polydipsia, polyuria, weightloss, and unresponsive, slow activity, listlessness, hair dull; situation above in MZ group,compared with DN, have varying degrees of improved; NC rats register as weight gain,good spirits, and flexible movement.2Compared with NC group, the kidney weight index, blood glucose, cholesterol,triglycerides, serum creatinine, blood urea nitrogen and24h urinary protein quantitativein the DN and MZ rats significantly increased,high-density lipoprotein (HDL) wassignificantly reduced, the difference was statistically significant (P <0.01); the aboveindicators of the MZ group Compared with DN group, had a significant improvement(excluding blood glucose, blood lipids), the difference was statistically significant (P<0.05or0.01).3.HE stained, observation by light microscopy：aorta：DN group: endothelial cellinjurying, infiltration of foam cells, deformation of disordered smooth muscle cell; thepathological changes above in MZ group reduced; NC group, the endothelial cells of thearterial wall arrange regularlly. Kidney tissue：DN group:kidney glomerular hypertrophy,mesangial matrix increased, cloudy swelling of renal tubular epithelial cells,inflammatory cell infiltration; the pathological changes above in MZ group reduced; NCgroup, glomerular, tubular structure was normal.4. U II/GPR14protein expression: aortic: Compared with NC group, DN group U-IIprotein expression in aortic was increased (P <0.01); compared with the DN group, theU-II protein expression in MZ group reduced (P <0.01). Renal tissue: Compared with NC group, glomerular U II/GPR14protein expression (the number of positivelystained cells) of DN group increased (P <0.05or P <0.01); compared with the DN group,the U II/GPR14protein expression of MZ group was decreased (P <0.05or P <0.01).5. Detection of U-II mRNA expression changes in kidney by RT-PCR: Compared withNC group, the U-II mRNA expression in DN and MZ groups obvious increased (P<0.01); compared with the DN group,the U-II mRNA expression in MZ group reduced(<0.01).Conclusion：1.The high expression of U-II/GPR14in aorta and renal tissue of ratssuggests that it may play an important role in kidney injury and atherosclerosisformation process of the diabetic rat. Mycophenolate mofetil can alleviate the pathologydamage of the aorta and kidney, and its mechanism may be related to the inhibition ofU-II/GPR14abnormal expression.2.Mycophenolate mofetil can improve the general station of diabetic nephropathy in rats,can reduce urinary protein and inhibit the deterioration of renal function. |
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