| I .The foundation of theoryWith the amelioration of modern people' living and change of dietetic structure, all of the world the incidence of Diabetic nephropathy(DN) is rising rapidly.There are about 16 millions diabetes mellitus(DM) patients,and there are about 800 thousands new patients.According to WTO's spot news of data forecast:there are 4 times DM patients in the future than today,there will be more than 240millions DM patients in the world. By the time of insulin turned up,DM is not the mainly minatory reason of the peoples health but its syndrome.DN is the familiar syndrome of DM,and it is the main season of the DM patients death. With the improvement of modern people' living, the incidence of DN is rising year by year and will become the leading cause of ESRD in the future 20 years. So how to treat and prevent the DN effectively is becoming the common concerned problem among international researcher.Changes of renal structure are the pathologic basis of DN, especially for the patients having obvious clinic symptom. In DN, all structure of the kidney appeared abnormal changes such as glomerulus, renal tubule, vessels, calyx and so on. The degree of abnormity determine the prognosis of DN patients. Now more and more importance are put into the early renal changes of DN. In this time the treatment and the drugs can alter the glomerular hemodynamics, metabolism of extracellular matrix(ECM), cell multiplication, cell hypertrophy and ameliorate the damage of glomerulus and renal tubule. So these can prevent and defer the incidence or course of DN. In view of this, many researchers focus on the early DN. In this time, appropriate clinic treatment may prevent and even reverse the pathological process of the kidney.The pathogenesis of DN is still not very clear today. Markedly progress had made in studying pathologic changes of DN and their related various factors in recent years. These researches indicated that pathogenesis of DN may be due to many kinds of compositive factors including glycometabolic disturbance and other factors resulting from this such as hemodynamics changes, cytokines, growth factors, and so on, and involve in many factors and various ways. Genetic susceptibility and hyperglycemia (environmental factor) are the beginning factors in causing DN. And their interactions result in the occurrence and progress of DN. Various cytokines may be the agency between above factors and the final pathologic changes of the kidney. Especially excessive expression of transforming growth factor(TGF) and platelet-derived growth factor are the key of the pathogenesisIn recent years, people payed more and more attention on the role of cytokines in pathogenesis of DN. Cytokines acted and restricted each other and made up of complicated cytokines network in pathogenesis of DN by the way of autocrine, paracrine and endocrine under the regulation of the fellow factors such as hyperglycemia, advanced glycation end products, protein kinase C, vessel active factors, changes of hemodynamics, and so on. Thereinto TGF-61 was key factor.In addition, reactive oxygen, nonenzyme glycation, lipid peroxidation material, hypertension, tissue anoxic and smoking may play some role in the pathogenesis of DN.The incidence of DN was rising in recent years, while western medicine still wasshort of perfect treatment measure. So it will be a concerned hotspot to explore effective treatment actively by the way of traditional Chinese midicine (TCM) . Although people has made some achievement in reporting the clinic curative effect observation and experience about treating DN with TCM and their some related curative mechanism researching, they are still far from making clear of complicated mechanism of TCM, especially for compound, in treating DN. The pathogenesis of DN is very complicated and involves many factors, which can act independently or interact each other resulting in the incidence of DN.DN is relate to Shenxiao of Xiaokou TCM. From of old, many doctors think it was due to weakness of lung, spleen and kikney. Its basic mechanism of TCM is Yinxuzaore, appearing in complete progress of incidence and development of disease. But we consider that prolonged illness always will consume Qi and injure Yin and implicate spleen and kidney, which will result in waning of spleen and kidney and injuring of Qi and Yin. Weak Qi is incapable of promoting blood. So prolonged illness may affect vas and result in stasis of blood stream, which is often found in DN. The weak spleen can't hoist Qingyang and lose conveyance, and then fine Qi of liquid and grist can not come into being. Because of weak kidney losing control of captain, fine substance downflows continuously and discharges outwards, which behaves with albuminuria. So we can treat DN by invigorating Qi and strengthening the spleen, nourishing kidney and Yin, impeling blood stream and dredging vas.II .Research contentsThis study focused on clinic and experiment.Firstly, collecting one passel early DN patients are investigated the influence of ShenkangWan(SKW) on patients serum lipid, super oxide dismutase ,malondialdehyde , nitric oxide,NO,renal fuction and the excretion rate of the 24h urine protein and albumin.Secondly, the early DN rat's glomerulus mesangial cells(MC) are investigated the influence of SKW onproliferation,excreting NO and TGF of by the method of serum pharmacology.Thirdly, the early DN rats are investigated the influence of SKW on general status, lipid peroxidation, reactive oxygen,etc,and observed the rat's renal pathology from morphologic by the optic and electronical microscope.Lastly,the early DN rats are detected renal and urinary transforming growth factor Bl(TGF-Bl) content by the mothod of molecular biology technique in order to evaluate the effect and its possible mechanism of SKW on DN. This way will embody the advantage of the TCM on DN.III.Methods and ResultsMethods:1.Collecting a group of cases of the early DN which were controled the level of blood glucose treated with SKW and Captopril respectively. After 6 and 12 weeks of treatment ,urine albumin excretion ratio(UAER),serum levels of blood glucose and lipid ,hepatic function and creatinine clearance(Ccr) were measured .2.The early diabetic rat model was made by a single introperitoneal injection of 55mg/kg streptozotocin(STZ).The rats renal were taken out germfreely,and the glomerulus mesangial cells were separated and cultivated.The cells were controlled in the GO periods,SKW's big,middling,small dose serum, Captopril serum and normal rat serum were interfused respectively to observe the cells form.and detect the cells proliferation,NO,TGF's excreting by spectrophotometer after cultivating 12,24,48 hours.3.The early diabetic rat model was replicated in the same way.The rats model were randomly assigned to four groups:the early DN group, Captopril -treated group,SKW-treated group and normal control group.The course of treatment lasted 4 weeks .The rats general status(psychosis,diet,hair color,weight amplitude,etc),blood and uric glucose,renal weight/body weight ratio ,excretion rate of the 24h uric protein and albumin,serum lipid(total cholesterol,trigyceride),UAER , serum creatinine(SCr),blood urea nitrogen(BUN),NO,super oxide dismutase(SOD), malondialdehyde(MDA) were monitored .The renal pathological lesions were also investigated with optical microscope and electron microscope .4.Four groups:the early DN group,Captopril-treated group,SKW-treated group and normal control group were treatment respectively 2 weeks and 4 weeks.Their renal tissue were detected the content of renal cytokines TGF-Bi by the methods of RT-PCR and immune histochemistry,meanwhile,urie TGF-Bi and excretion rate of uric albumin were detected by ELISA.Results:l.Based on controlling the blood glucose availability, SKW-treated group's total ratio of effective is 92.5%, Captopril-treated group is 72.5%.Compared with two groups, SKW-treated group is obviously excel to Captopril(P<0.05).SKW can reduce the excretion rate of uric albumin,increase serum NO,increase serum SOD,eliminate effectively reactive oxygen,reduce total cholesterol,trigyceride.there are no toxicity and side-effect.2.The model rats blood glucose are exceed to 13.8mmol/L,urie gloucose are from ++~++++,uric protein's test paper is negative.Compared with normal group excreting ratio of uric albumin have prominence difference(P<0.01),uric amount is manifold.Their symptom are energy cachexia,slowness reaction,slow action,hair stand and lackluster,their back arch and body crouch,urinate manifold,eating water and food increase.renal slices can be seen a majority of glomerulus increasing,swelling,bleeding,GBM incrassation,part of glomerulus MC hyperplasia, mesangial width increasing,cell hypertrophy and vacuole denaturalization in tubulo.There have not glomerulus cirrhosis.3.Compared with normal serum,big,middling,small dose serum of SKW can control the early DN rats' MC proliferation and TGF-Bi excreting.They can accelerateNO excreting,and these function can boost up with time and drug's chroma elevatory.4.SKW can improve the early DN rats' general status effectively,alleviate obese renal, alleviate change degree of renal pathology.Compared with the model group,SKW can reduce evidently the early DN rats' uric protein,excreting ratio of uric albumin(P<0.01).In the experiment,cotents of NO descend evidently in the renal tissue and serum of model rats(P<0.01).Cotents of NO ascend evidently in the renal tissue and serum of SKW-treated and Captopril-treated rats.Although abnormality these are,but results have the meaning of statistics. Compared with the model group,SKW-treated and Captopril-treated group have prominence difference (P<0.05). Compared with the model group,SKW-treated groups' blood lipid have the meaning of statistics(P<0.05).There have the obvious phenomena of active SOD descending and MDA's value ascending in the renal tissue and serum of the model rats(P<0.01). There also have the obvious phenomena of active SOD descending and MDA's value ascending in the renal tissue and serum of theSKW-treated groups, and the results have the meaning of statistics though abnormality(P<0.05).Captopril-treated groups have the function of active SOD descending and MDA's value ascending,but the results haven't prominence difference.5.The model groups' uric TGF-Gurenal tissue TGF-61 protein and TGF-6] mRNA expression are bigger than the normal groups'(P<0.01).After treatment the SKW-treated groups' uric TGF-Bi ,renal tissue TGF-Bi protein and TGF-Bi mRNA expression are samller than the model groups'(P<0.01).IV. Conclusion1. Based on controlling the blood glucose availability,SKW have better function of therapy and protection to the early DN patients in the clinic.2.SKW's big,middling,small dose can control the early DN rats' MC proliferation, TGF-Gi excreting.and they can accelerate NO excreting.These function can boost upwith time and drug's chroma elevatory.3. SKW can improve the early DN rats' general status effectively,alleviate obese renal, protect the renal lesion in some extents,reduce evidently the early DN rats' uric protein and excreting ratio of uric albumin, descend evidently the cotents of NO in the renal tissue and serum of model rats,descend total cholesterol and trigyceride,improve the lipid metabolize,descend SOD's content ,ascend MDA's content in the renal tissue and serum of the early DN rats.It cue SKW could alleviate the renal lesion with oxidative stress by eliminating superoxide anion.4.SKW can descend uric TGF-Bi excreting and control renal tissue TGF-Bi protein andTGF-6i mRNA over-expression. |
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