HTG和糖尿病复合地鼠模型的建立及诱发肾损伤机制研究
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摘要
现已证实高甘油三酯血症是动脉粥样硬化等多种心脑血管疾病的独立危险因子,目前富含甘油三酯的脂蛋白对肾脏的致病性也逐渐得到重视,本研究首次建立糖尿病高甘油三酯血症金黄地鼠模型,并探讨了高甘油三酯对肾脏的损伤机制。采用链脲佐菌素注射联合高脂高胆固醇饮食饲喂的方法,诱导地鼠肝脏甘油三酯分泌增加,清除减慢,血浆甘油三酯显著升高,建立了饮食诱导的非转基因高甘油三酯血症动物模型。通过对此模型血液流变学、肾功能、肾脏病理组织学变化等的检测,发现动物出现蛋白尿、肾脏肥大、肾小球系膜基质扩张、糖原沉积等肾脏病理改变,表明高甘油三酯在诱发早期糖尿病肾损伤中发挥着重要的作用。进一步研究发现高甘油三酯致肾损伤的机制为脂代谢关键基因SREBP-1c表达上调、TGF-β通路活化及氧化应激增加,导致高甘油三酯血症引发肾脏损伤。SREBP-1c表达的上调引起地鼠脂肪酸合成增加,脂质沉积于肝脏、肾脏,启动了肾损害的关键步骤,同时致纤维化生长因子TGF-β、CTGF、PAI-1及炎性因子IL-6、TNF-α上调,证实高甘油三酯血症通过激活TGF-β通路导致肾小球病变,另外,高甘油三酯血症加速了高糖所致的氧化应激,形成丙二醛等脂质过氧化物加速肾脏损伤。
Diabetic nephropathy (DN), a serious complication of diabetes, is the changes of renal structure and function that caused by diabetic microangiopathy. It is also the major cause of morbidity in diabetes. DN patients often have lipid metabolic disorder and abnormal lipoprotein composition. The reserch between dyslipidmia and renal lesion has become a hot topic. The current study has confirmed the pathogenicity of dyslipidemia to the illed kidney, however, the present research mainly focused on the effect of hypercholesterinemia, especially small/dense LDL and ox-LDL in kidney disease. Since hypertriglyceridemia has been confirmed to be the independent risk factor in artherosclerosis and coronary arteriosclerotic heart disease, triglyceride rich lipoprotein, such as very low density lipoprotein, intermediated-density lipoprotein received attention in the pathogenesis of kidney disease. People realized that triglyceride, as well as cholesterol may be also an independent risk factor, and plays an important role in the development and prognosis in kidney disease. The mechanism on how hypertriglyceridemia works in the development of diabetic nephropathy have not yet been fully elucidated. This is partly because of a lack of proper hypertriglyceridemia model. Lipid metabolism of mice and rat are quite different from that in human being when treated with high calory diet, plasma triglyceride and cholesterol level can’t reach high and also can’t maintain for a long time, so mice and rat are not suitable for lipid study. Genetically modified animals presented hypertriglyceridemia, however, the survival rate is low and they are not easily available. So it is very important to establish an appropriate animal model for further studies of mechanism on triglyceride toxicity in kidney.
In the present study, Syrian golden hamsters were used as an animal model to study diabetic dyslipidemia regarding their hepatic lipid metabolism is similar to that found in human. Through streptozocin injection and high fat/cholesterol diet fed, we established a diabetic hypertriglyceridemia animal model mimicking diabetic dyslipidemia patients in a short period of time, with the advantage of shorter time-consuming, higher plasma lipid concentration and easier operation. Further, we confirmed the toxicity of HTG on kidney. Changes in haemodynamics, lipid metabolism, inflammation reaction, oxidative stress were studied to explain the mechanism of hypertriglyceridemia in the development of diabetic nephropathy.
In this study, diet-induced/non-genetically modified HTG animal model was established by injection of streptozotocin and fed with a diet enriched with fat and cholesterol. Plasma triglyceride and cholesterol levels reached to 1000mg/dl in hamsters fed with high fat/cholesterol diet for 4 weeks, however, in diabetic hamsters fed with high fat/high cholesterol diet (D-HFHC), plasma triglyceride concentration reached to 20000mg/dl, plasma cholesterol concentration reached to 4500mg/dl, which indicates that diabetes and cholesterol in diet plays an important role in inducing hypertriglyceridemia, and it depends on saturated fatty acid added in diet. Enlargement and lipid deposition in liver were found in D-HFHC group, whilst HDL-C, MDA levels increased, indicates a high risk for artherosclerosis and other cardial-cerebrovascular disease. The main reason of high calorie diet induced hypertriglyceridemia in diabetic hamster is that the clearance of triglyceride decreased 33 times, and liver triglyceride secretion increased about 6 times. Meanwhile, liver fatty acid synthesis increased, which induced lipid deposition in liver and kidney. Hemorrheology mainly studies the blood flow and blood cell deformation, vascular system diseases may occure when heart, blood vessels and blood volume under normal circumstances, just because abnormity in hemorheological characteristics. The present study showed that hypertriglyceridemia induced changes in hemorheological characteristics, such as high blood viscosity, decreased erythrocyte deformability, increased erythrocyte osmotic fragility, decreased electronegativity et al, all these hemorheological changes and HTG, low HDL-C raised susceptibility of diabetic microangiopathy including diabetic nephropathy.
In order to explain the effects of hypertriglyceridemia in diabetic renal injury, normal or diabetic hamsters were fed with high fat diet (HF), high cholesterol diet (HC), and high fat diet/high cholesterol diet (HFHC). 2 weeks after diet treatment, diabetic hamsters exhibited increased kidney weight/body weight ratio and albumin in urine. Although plasma TC levels are similar between diabetic hamsters fed with high cholesterol diet and diabetic hamsters fed with high fat/high cholesterol diet, the latter has an evident renal pathology change of diabetic nephropathy, eg. renal hypertrophy, lipid deposition, proliferation of glomerular mesangial cell, extracellular matrix(ECM)deposition, fibrosis etal. So it is confirmed that hypertriglyceridemia plays an important role in the early development of diabetic nephropathy. mRNA expression of cytokines indicated that the increase of SREBP-1 upregulated TGF-β, TGF-βwas secreted by mesangial cell, it can promote cell hypertrophy, increase the production of extracellular matrix, it can also reduce the degradation of matrix by increasing the activity of matrix catabolic enzymes inhibitor, so it is thought to be the key factor of kidney lesion. Besides, PAI-1 and CTGF, which are the main factors in kidney fibrosis and deposition of ECM also increased, promoted renal fibrosis. Increased TNF-αand IL-6 also plays an important role. Upregulation of NADPH oxidase subunit p47phox, p467phox and Nox4 indicated that oxidative stress was also involved. Renal oxidative stress can induce apoptosis, dysfunction of endothelial cell, white blood cell infiltration and hypercoagulabale state. In conclusion, deposition of lipid in glomerular caused monocyte-macrophages aggregation and activation. Changes of renal hemodynamics, activation of cytokines and vasoactive substances, inhibition of ECM degradation and increase of oxidative stress are the reason that hypertriglyceridemia caused diabetic nephropathy lesion.
Disorder of lipid metabolism is a common clinical situation in primary and secondary renal disease; it is also the independent pathogenic factor. Body reaction of dyslipidemia is complex, the present study provided experimental evidence and laid the foundation for study the relationship among diet induced hypertriglyceridemia, kidney lesion, fatty liver, fat and insulin resistence.
Diabetic nephropathy (DN), a serious complication of diabetes, is the changes of renal structure and function that caused by diabetic microangiopathy. It is also the major cause of morbidity in diabetes. DN patients often have lipid metabolic disorder and abnormal lipoprotein composition. The reserch between dyslipidmia and renal lesion has become a hot topic. The current study has confirmed the pathogenicity of dyslipidemia to the illed kidney, however, the present research mainly focused on the effect of hypercholesterinemia, especially small/dense LDL and ox-LDL in kidney disease. Since hypertriglyceridemia has been confirmed to be the independent risk factor in artherosclerosis and coronary arteriosclerotic heart disease, triglyceride rich lipoprotein, such as very low density lipoprotein, intermediated-density lipoprotein received attention in the pathogenesis of kidney disease. People realized that triglyceride, as well as cholesterol may be also an independent risk factor, and plays an important role in the development and prognosis in kidney disease. The mechanism on how hypertriglyceridemia works in the development of diabetic nephropathy have not yet been fully elucidated. This is partly because of a lack of proper hypertriglyceridemia model. Lipid metabolism of mice and rat are quite different from that in human being when treated with high calory diet, plasma triglyceride and cholesterol level can’t reach high and also can’t maintain for a long time, so mice and rat are not suitable for lipid study. Genetically modified animals presented hypertriglyceridemia, however, the survival rate is low and they are not easily available. So it is very important to establish an appropriate animal model for further studies of mechanism on triglyceride toxicity in kidney.
In the present study, Syrian golden hamsters were used as an animal model to study diabetic dyslipidemia regarding their hepatic lipid metabolism is similar to that found in human. Through streptozocin injection and high fat/cholesterol diet fed, we established a diabetic hypertriglyceridemia animal model mimicking diabetic dyslipidemia patients in a short period of time, with the advantage of shorter time-consuming, higher plasma lipid concentration and easier operation. Further, we confirmed the toxicity of HTG on kidney. Changes in haemodynamics, lipid metabolism, inflammation reaction, oxidative stress were studied to explain the mechanism of hypertriglyceridemia in the development of diabetic nephropathy.
In this study, diet-induced/non-genetically modified HTG animal model was established by injection of streptozotocin and fed with a diet enriched with fat and cholesterol. Plasma triglyceride and cholesterol levels reached to 1000mg/dl in hamsters fed with high fat/cholesterol diet for 4 weeks, however, in diabetic hamsters fed with high fat/high cholesterol diet (D-HFHC), plasma triglyceride concentration reached to 20000mg/dl, plasma cholesterol concentration reached to 4500mg/dl, which indicates that diabetes and cholesterol in diet plays an important role in inducing hypertriglyceridemia, and it depends on saturated fatty acid added in diet. Enlargement and lipid deposition in liver were found in D-HFHC group, whilst HDL-C, MDA levels increased, indicates a high risk for artherosclerosis and other cardial-cerebrovascular disease. The main reason of high calorie diet induced hypertriglyceridemia in diabetic hamster is that the clearance of triglyceride decreased 33 times, and liver triglyceride secretion increased about 6 times. Meanwhile, liver fatty acid synthesis increased, which induced lipid deposition in liver and kidney. Hemorrheology mainly studies the blood flow and blood cell deformation, vascular system diseases may occure when heart, blood vessels and blood volume under normal circumstances, just because abnormity in hemorheological characteristics. The present study showed that hypertriglyceridemia induced changes in hemorheological characteristics, such as high blood viscosity, decreased erythrocyte deformability, increased erythrocyte osmotic fragility, decreased electronegativity et al, all these hemorheological changes and HTG, low HDL-C raised susceptibility of diabetic microangiopathy including diabetic nephropathy.
In order to explain the effects of hypertriglyceridemia in diabetic renal injury, normal or diabetic hamsters were fed with high fat diet (HF), high cholesterol diet (HC), and high fat diet/high cholesterol diet (HFHC). 2 weeks after diet treatment, diabetic hamsters exhibited increased kidney weight/body weight ratio and albumin in urine. Although plasma TC levels are similar between diabetic hamsters fed with high cholesterol diet and diabetic hamsters fed with high fat/high cholesterol diet, the latter has an evident renal pathology change of diabetic nephropathy, eg. renal hypertrophy, lipid deposition, proliferation of glomerular mesangial cell, extracellular matrix(ECM)deposition, fibrosis etal. So it is confirmed that hypertriglyceridemia plays an important role in the early development of diabetic nephropathy. mRNA expression of cytokines indicated that the increase of SREBP-1 upregulated TGF-β, TGF-βwas secreted by mesangial cell, it can promote cell hypertrophy, increase the production of extracellular matrix, it can also reduce the degradation of matrix by increasing the activity of matrix catabolic enzymes inhibitor, so it is thought to be the key factor of kidney lesion. Besides, PAI-1 and CTGF, which are the main factors in kidney fibrosis and deposition of ECM also increased, promoted renal fibrosis. Increased TNF-αand IL-6 also plays an important role. Upregulation of NADPH oxidase subunit p47phox, p467phox and Nox4 indicated that oxidative stress was also involved. Renal oxidative stress can induce apoptosis, dysfunction of endothelial cell, white blood cell infiltration and hypercoagulabale state. In conclusion, deposition of lipid in glomerular caused monocyte-macrophages aggregation and activation. Changes of renal hemodynamics, activation of cytokines and vasoactive substances, inhibition of ECM degradation and increase of oxidative stress are the reason that hypertriglyceridemia caused diabetic nephropathy lesion.
Disorder of lipid metabolism is a common clinical situation in primary and secondary renal disease; it is also the independent pathogenic factor. Body reaction of dyslipidemia is complex, the present study provided experimental evidence and laid the foundation for study the relationship among diet induced hypertriglyceridemia, kidney lesion, fatty liver, fat and insulin resistence.
引文
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