| Chronic kidney disease (DKD) is a serious hazard to human health and hasbecome a global public health problem. Diabetes is a major cause of chronic kidneydisease. Approximately a third of patients with diabetes develop DKD and theprevalence of diabetic-induced DKD increased in direct proportion to the prevalenceof diabetes itself in the global. Diabetic nephropathy is one of the most common andserious diabetic micro-vascular complications, eventually leading to end-stage renaldisease and accounting for nearly40%of new cases. Type2diabetes accounts forapproximately90~95%of all diagnosed cases, and30%to40%of which willeventually develop end-stage renal failure. The pathogenesis of type1and type2diabetic kidney diseases may differ. Among many pathogenesis of type2diabetes,disorders of glucose and lipid metabolism are the initial factors, followed by inducedhyperglycemia and lipid abnormalities, leading to advanced glycation end productformation, oxidative stress and inflammation, and eventually cause type2diabetickidney disease. Extensive studies show that oxidative stress is a common mechanismof the diverse complications of diabetes, and inflammation is a key factor contributingto the sustainable development of the disease. Recently, the incidence of diabeticnephropathy in our country is increasing. Therefore, the prevention and therapy ofdiabetic nephropathy has become an urgent problem in The Medical Profession.Research background:High-dose of radiation clearly produces deleterious consequences to humanbeings. However, low-dose radiation (LDR) induces adaptive response e.g. promotionof DNA damage repair, regulation of a variety of cellular signal transductionpathways, enhancement of expression of endogenous antioxidant enzymes. Withfurther research, a large number of clinical practices suggest that LDR could reduceinflammation and is applicable for the treatment of chronic inflammatory diseases.Fibroblast growth factor21(FGF21) is a relatively new metabolic regulationfactor that regulates glucose and lipid metabolism and was closely associated withobesity, type2diabetes and other metabolic diseases. FGF21biological activitiesincluded: enhancing insulin sensitivity, promoting peripheral tissues such as adipose tissue to absorb glucose, lowering blood sugar, improving the function of pancreatic βcells and lipoprotein profiles and so on.Given biological effects of LDR and FGF21, we plan to explore whether theeffects of LDR ccombined with FGF21on the kidney disease in type2diabetes issuperior to both alone.Research objectives:1. To establish mouse model of type2diabetes;2. To explore the effects of LDR on the kidney disease in type2diabetes mice;3. To explore the effects of FGF21on the kidney disease in type2diabetes mice;4. To compare the effects of LDR ccombined with FGF21and both alone on thekidney disease in type2diabetes.Research method:Male C57BL/6J mice (18~20g of body-weight) were allowed to acclimate for1week, and fed with a high-fat diet (40%energy from fat) for12weeks to induceinsulin resistance, followed by a single intraperitoneal injection of a low dose of STZ(50mg/kg) to decrease compensatory insulin secretion disorders producinghyperglycemia. The model is similar to that of non-insulin-dependent diabetesmellitus (human type2diabetes). Diabetic mice were randomly selected for treatmentof LDR (12.5mGy/min,25mGy,50mGy and75mGy/day respectively, irradiationonce every other day, for4weeks and8weeks) and treatment of FGF21(0.5mg/kg,1.5mg/kg and2.5mg/kg respectively, administration once daily, for4weeks and8weeks). At the end of the experiment, body weight, blood glucose and insulinsensitivity were evaluated. Twenty-four-hour urine collections and serum wasobtained for detection of urinay protein, urinay alumin, urinay creatinine and lipidsusing enzyme-linked immunosorbent assay and automatic biochemical analyzer,respectively. Renal tissues were obtained for detection of histopathological changes,expression levels of antioxidant enzymes and inflammatory cytokines bymorphological staining, quantitative real-time PCR (qRT-PCR), Western-blot andimmunohistochemistry staining approaches. Finally, we choose the optimal treatmentcondition (50mGy irradiation for4weeks and1.5mg/kg administration of FGF21for8weeks) to explore whether the effects of LDR combined with FGF21on the kidneydisease in type2diabetes is superior to both alone.Research results:1. LDR could inhibit weight loss and dyslipidemia, enhance insulin sensitivity and improve kidney structure and function in mice with type2diabetes, but not affecton blood sugar level. Meanwhile, the effects of irradiation at50and75mGy fourweeks were better than that of others. However,50and75mGy irradiationtreatment for8weeks, except for25mGy, caused different levels of toxic sideeffects.2. Each dose of irradiation for4weeks could significantly upregulate the expressionof antioxidant factors Nrf-2、SOD-1、HO-1、NQO-1.50mGy and75mGy, but not25mGy irradiation for4weeks could significantly reduce levels of inflammatorycytokines ICAM-1、PAI-1、TNF-α and oxidative stress markers3-NT and MDA.When irradiation time was extended to8weeks, although each dose could remainsignificantly upregulating antioxidant factors,50mGy and75mGy could notinhibit the expression of the aboved inflammatory cytokines. These suggesteddifferent doses of a single dose and cumulative dose play a different role inorganisms.3. FGF21could significantly decrease blood glucose level and improve insulinsensitivity and alleviate renal structural changes and dysfunction induced by type2diabetes.4. FGF21could significantly downregulate expression levels of antioxidant factorsNrf-2, SOD-1, HO-1and NQO-1and significantly reduce levels of the aboveinflammatory factors and oxidative stress markers3-NT and MDA.5. Compared with both alone treatment, LDR combinined with FGF21treatmentsignificantly improved insulin sensitivity and further inhibited dyilipidemia andrenal pathological structural changes induced by diabetes, slowing the process ofkidney disease of type2diabetes.6. Compared with both alone treatment, LDR combinined with FGF21treatmentfurther significantly reduced inflammatory cytokines ICAM-1, PAI-1and TNF-αand oxidative stress marker3-NT and MDA. Furthermore, there may be asynergistic effect between effect of LDR on antioxidant function and of FGF21onregulation of glucose and lipid metabolism.Conclusions:In short,50mGy treatments for4weeks and1.5mg/kg of FGF21treatment for4or8weeks could significantly inhibit renal pathological structure changes and renaldysfunction induced by type2diabetes. Meanwhile, LDR combined with FGF21 treatment is better than any of a single treatment in improving renal structure andfunction, effectively slowing the progession of type2diabetic kidney disease. Inaddition, our study is designed to provide theoretical basis for treatment of type2diabetes and its clinical complications. |
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