| Objective:With the improvement of people's life and aged of social population ,diabetic nephropathy(DN) rising year by year with morbidity of diabetes mellitus(DM), has already been one of the main etiological factors of end stage of renal failure(ESRF) in China. So now researching the pathogenesis,prevention and therapy of diabetic nephropathy becomes an important topic to the nephrologists.The MAPKs is a serine/threonine protein kinases existing in the body of vertebra animals extensively.It is one of the important kinase cascades that transmit extracellular stimuli to cell nucleus causing various cellular functions.It is activated via Ras-dependent intracellular signaling pathway associated with tyrosine-kinase-coupled receptors.Many physiological courses have relevance with the regulation of MAPKs signal transduction pathway,such as growth,development,split,death and synchronization of intercellular function.As has been identified,there are four MAPK pathways in eukaryotic cells,namely the extracellular signal-regulated kinase 1 and 2(ERK1/ERK2,p44/p42),the c-Jun N-terminal kinase/stress-activated protein kinase(JUN/SAPK),the p38MAPK,and the ERK5.MAPKs is an important kinase leading to cell proliferation and protein synthesis,each of whose subgroup modulates different signaling events either alone or in concert with other pathway.Among them,ERK1 and ERK2 are the most extensively studied,which is the prototypical MAPK pathway activated by mitogenic growth factor stimulation of receptor tyrosine kinase.Studies indicate that ERK1/ERK2 is activated in the mesangial cells cultured under high glucose condition via activation of protein kinase C(PKC).We have observed the activation of ERK1 and ERK2 in mesangial cells stimulated by high glucose.Activated MAPKs can lead to the enhancement of arachidonic acid release and upregulation prostaglandin E2 by the activation of cPLA2 in cell plasm.These changes might be related to the expansion of afferent glomerular arteriole,glomerular hyperfusion and hyperfiltration,and lead to the development of glomerular lesions in diabetes. Now many studies have demonstrsted the cause of DN is resulted from comprehensive actions of lots of cytokine factors, growth factors and various kinds of abnormal reactions to high glucose.Among them stimulated by high glucose transforming growth factor-(1(TGF-(1)can cause cell hypertrophy and accumulation of extracellular matrix(ECM),which contains collagen,fibronectin(FN), laminin (LN),and tenascin,and it also plays an important role in the course of glomerular sclerosis by upregulating geneexpression of ECM proteins,such as collagen,fibronectin,in mesangial cells.Recently in human mesangial cells we found both ERK and JNK MAPK kinases are activated by TGF-(1 treatment of mesangial cells,while the protein levels of both ERKs and JNKs were not significantly affected by TGF-(1 treatment.So in order to investigate the activity of ERKs pathway ,the level of TGF-(1,renal function,blood lipids, histologic construction and the degree of diabetic nephropathy progress were studied from the renal cortex of experimental diabetic rats.In addition,by the medding trials in diabetic rats,from molecular level we analyzed the following questions: if 3-hydroxy-3-methylgutaryl(HMG-CoA) reductase inhibitor,fluvastatin,has a preventive effect on the development of diabetic nephropathy in STZ-induced diabetic rats independently of the effect of regulating serum lipid levels;what is the action of ERKs pathway in the progression of DN as a signal transduction pathway.Finally, the theoretic basement was advanced for preventing and curing human DN. Methods: male Sprague-Dawley rats weighting 150-190g were made diabetes mellitus by a single celioinjection of streptozotocin(STZ) bought from Sigma(60mg/kg body weight) in 0.1mmol/L citrate buffer(pH 4.5).Rats receiving an injection of citrate buffer were used as control group.The levels of blood glucose were determined 2 days after the injection of STZ or vehicle,and rats with bloodgluc...
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