The Preventive And Therapeutic Effects Of Astragalus Saponin I And Bendazac Lysine On Early Stage Of Diabetic Nephropathy And Their Mechanisms

BackgroundDiabetic nephropathy(DN) is now a leading cause of end-stage renal failure in many countries. More than 30 % of diabetes mellitus patients develop clinically evident DN 10 to 20 years from the onset of diabetes mellitus. DN seems to occur as a result of interaction of metabolic and haemodynamic factors. Glucose dependent pathways are activated within the diabetic kidney. These include increased oxidative stress, renal polyol formation, advanced glycated end-products (AGEs) accumulation, and pro-sclerotic cytokines, such as transforming growth factor (TGF-1). These pathways ultimately lead to increased renal albumin permeablility and extracellular matrix accumulation which result in increasing proteinuria, glomerulosclerosis and tubulointerstitial fibrosis. Therefore, besides the traditional therapeutic methods, some novel strategies have been focused very recently. Inhibitors of advanced glycation and aldose reductase(AR) are at present under experimental and clinical investigation.Radix Astragali, the root of Astragalus membranaceus (Fisch.) Bunge, is a crude drug widely used in traditional Chinese medicine. Astragalus Saponin I (ASI) is one of the effective compounds from Radix Astragali. Studies have demonstrated that Astragalus membranaceus has inhibitory effect on oxidative stress and the secretion of insulin and C-peptide. These data suggest that extract of Astragalus or ASI might have beneficial effects on DN, which was consistent with the fact that Astragalus membranaceus was frequently used for the treatment of DM in clinic. Bendazac lysine(BDL) is one of a number of agents which have been introduced for themanagement of cataract. Its principal effects are to inhibit the denaturation of proteins. Several studies show that BDL has inhibitory effect on AR, a main enzyme in polyol pathway, antioxidative effect and inhibitory effect on glycosylation, all of which are included in the progression of DN. Therefore, it is worthwhile for us to explore its potential effects on preventing the progressive cause of DN.Up to now, most of anti-DN drugs usually influence only one of pharmacological targets in complex pathological mechanism of DN, therefore, their therapeutic effects are not strong enough, and extensive adverse reactions exist. Thus, it is worthwhile for us to study the mechanisms of ASI and BDL as anti-DN agents and make preparation for the drug development. Furthermore, on the basement that the difference effective targets and strength of ASI and BDL on DN, we observe the probable synergetic effects of coadministration of ASI and BDL, and evaluated its potential therapeutic effects on DN. This trial will be beneficial to the anti-DN drug development.Aims1 To provide the experimental data for development of novel preparation of Hangqi, and to find the effective targets of ASI on DN, we observe the therapeutic effects of ASI on early stage of DN rats in several aspects.2 To explain the pharmacological mechanisms of ASI on DN-therapy, the relationship of hyperglycemia and oxidative stress, the relationship of oxidative stress and the symptoms of DN, and the effects of ASI on the symptoms of DN are to be studied.3 To validate our hypothesis that BDL might have therapeutic effects on DN and find the effective pharmacological points of BDL, and therefore, to provide the experimental evidence for the novel indication of BDL, we observe the therapeutic effects of BDL on early stage of DN rats.4 We observe the relationship of hyperglycemia and oxidative stress, the relationship of oxidative stress and the symptoms of DN, and the effects of BDL on the symptoms of DN, in order to explain the pharmacological mechanisms ofBDL on DN-therapy.5 To observe and compare the inhibitory type and inhibitory constant of ASI and BDL on AR extracted from bovine lens.6 On the base of therapeutic mechanisms of ASI and BDL, we are going to investigate the synergetic effects on DN of coadiministration of ASI and BDL on cultured rat mesangial cells an...