Novel Models of Diabetic Nephropathy

糖尿病肾病的新模型

基本信息

批准号：
7682089
负责人：
MOSHE LEVI
金额：
$ 30.81万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-30 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7682089
关键词：
Advanced Glycosylation End Products Albuminuria Attenuated Binding Proteins Biochemical Blood Pressure Breeding Calmodulin Carbohydrates Cholesterol Crossbreeding Development Diabetic Nephropathy Diabetic mouse Diet Diffuse Enzymes Fibrosis Genetic Glomerular Filtration Rate Growth Factor Inflammation Inflammatory Injury Insulin Insulin Resistance Insulin-Dependent Diabetes Mellitus Kidney Knockout Mice Lipids Mediating Modeling Mus Non-Insulin-Dependent Diabetes Mellitus Obesity Oxidative Stress Pathogenesis Phenotype Play Predisposition Proteinuria Response Elements Role SRE-1 binding protein SRE-2 binding protein Structure of glomerular mesangium Transgenes Transgenic Mice Triglycerides base carbohydrate metabolism cytokine db/db mouse diabetic glomerulosclerosis mouse model novel overexpression podocyte prevent promoter protein expression receptor

Advanced Glycosylation End Products Albuminuria Attenuated Binding Proteins Biochemical Blood Pressure Breeding Calmodulin Carbohydrates Cholesterol Crossbreeding Development Diabetic Nephropathy Diabetic mouse Diet Diffuse Enzymes Fibrosis Genetic Glomerular Filtration Rate Growth Factor Inflammation Inflammatory Injury Insulin Insulin Resistance Insulin-Dependent Diabetes Mellitus Kidney Knockout Mice Lipids Mediating Modeling Mus Non-Insulin-Dependent Diabetes Mellitus Obesity Oxidative Stress Pathogenesis Phenotype Play Predisposition Proteinuria Response Elements Role SRE-1 binding protein SRE-2 binding protein Structure of glomerular mesangium Transgenes Transgenic Mice Triglycerides base carbohydrate metabolism cytokine db/db mouse diabetic glomerulosclerosis mouse model novel overexpression podocyte prevent promoter protein expression receptor

展开

项目摘要

DESCRIPTION (provided by applicant): Background: In a) OVE26 mice with type 1 diabetes, b) C57BI/6 mice with diet induced obesity and insulin resistance, and c) db/db mice with type 2 diabetes mellitus, we have found increased renal expression of the transcriptional factors, i) the sterol regulatory element binding proteins 1 and 2 (SREBP-1 and SREBP-2), and ii) the carbohydrate response element binding protein (ChREBP), which result in increased synthesis and accumulation of triglyceride and cholesterol. The lipid accumulation is associated with development of robust glomerulosclerosis, tubulointerstitial fibrosis, and proteinuria. We have also found that the Farnesoid X Receptor (FXR) is highly expressed in the kidney and the expression of FXR and its target enzymes is decreased in the diabetic kidney. Furthermore we have determined that FXR is an important regulator of SREBP-1 and ChREBP expression as well as oxidative stress, advanced glycation end products (AGEs/RAGE), pro-inflammatory cytokines, and fibrosis inducing growth factors. Hypothesis: Based on these finding we propose that FXR plays an important role on the pathogenesis of diabetic nephropathy. We hypothesize that deletion of FXR will markedly enhance and overexpression of FXR will attenuate diabetic nephropathy in mouse models of type 1 (OVE26) and type 2 (db/db) diabetes. Mouse Model 1: A) We will generate FXR knockout mice, currently on the C57BI/6 genetic background, on Background: In a) OVE26 mice with type 1 diabetes, b) C57BI/6 mice with diet induced obesity and insulin the FVB, and if need be and DBA/2J genetic backgrounds, 2 genetic backgrounds that have been documented to have increased susceptibility to diabetic nephropathy. B) We will then cross breed FXR KO mice on FVB background with i) OVE26 mice (type 1 diabetes) on FVB background or ii) db/db mice (type 2 diabetes) on FVB background to determine if FXR deletion accentuates and accelerates diabetic nephropathy. C) We will generate renal podocyte specific FXR knockout mice on FVB background using the Lox-Cre approach (FXRf/f mice crossed with Nphs2 Cre mice). D) We will then crossbreed podocyte FXR KO mice with i) OVE26 mice or ii) db/db mice. Mouse Model 2: A) We will generate renal podocyte specific conditional and inducible FXR transgenic mice in the FVB Background. B) We will then crossbreed the podocyte specific FXR transgenic mice with OVE26 or db/db mice to determine if increased expression of FXR attenuates or prevents diabetic nephropathy. Phenotyping: In these mice we will determine a) the manifestation of diabetic nephropathy, including glomerular filtration rate, glomerulosclerosis, tubulointerstitial fibrosis, and proteinuria and b) the cellular and biochemical mechanisms that mediate diabetic renal injury including lipid and carbohydrate metabolism, inflammation, fibrosis, oxidative stress, and AGEs/RAGE.

描述（由申请人提供）： Background: In a) OVE26 mice with type 1 diabetes, b) C57BI/6 mice with diet induced obesity and insulin resistance, and c) db/db mice with type 2 diabetes mellitus, we have found increased renal expression of the transcriptional factors, i) the sterol regulatory element binding proteins 1 and 2 (SREBP-1 and SREBP-2), and ii) the碳水化合物反应元件结合蛋白（CHREBP），导致甘油三酸酯和胆固醇的合成和积累增加。脂质的积累与稳健的肾小球硬化，微管间质纤维化和蛋白尿的发展有关。我们还发现，Farnesoid X受体（FXR）在肾脏中高度表达，FXR的表达及其靶酶在糖尿病肾脏中降低。此外，我们已经确定FXR是SREBP-1和CHREBP表达的重要调节剂，以及氧化应激，晚期糖基化终产物（Ages/Rage），促炎性细胞因子和纤维化诱导生长因子。假设：根据这些发现，我们建议FXR在糖尿病肾病的发病机理中起重要作用。我们假设FXR的缺失将显着增强和过表达FXR会减弱1型（OVE26）和2型（DB/DB）糖尿病的小鼠模型中的糖尿病性肾病。鼠标模型1：a）我们将生成FXR敲除小鼠，目前在C57BI/6遗传背景上，背景：在a）具有1型糖尿病的OVE26小鼠中，b）C57BI/6小鼠具有饮食诱导的肥胖症和胰岛素的饮食诱导的FVB，如果需要的话，以及遗传背景，2J/2J遗传背景，已有遗传性背景，已有遗传性背景，已经遗传了遗传性的背景，该遗传性均为疾病。肾病。 b）然后，我们将在FVB背景上与FVB背景的I）OVE26小鼠（1型糖尿病）在FVB背景或II）上交叉繁殖FXR KO小鼠，或者II）在FVB背景上的DB/DB小鼠（2型糖尿病），以确定FXR缺失的加注和加速糖尿病肾病。 c）我们将使用LOX-CRE方法（与NPHS2 CRE小鼠交叉的FXRF/F小鼠）在FVB背景上生成肾足细胞特异性FXR敲除小鼠。 d）然后，我们将与I）OVE26小鼠或II）DB/DB小鼠交叉杂交的Podocyte FXR KO小鼠。小鼠模型2：a）我们将在FVB背景下生成肾脏足细胞特异性和诱导的FXR转基因小鼠。 b）然后，我们将用OVE26或DB/DB小鼠将足细胞特异性FXR转基因小鼠交叉杂交，以确定FXR衰减表达的增加还是预防糖尿病性肾病。 Phenotyping: In these mice we will determine a) the manifestation of diabetic nephropathy, including glomerular filtration rate, glomerulosclerosis, tubulointerstitial fibrosis, and proteinuria and b) the cellular and biochemical mechanisms that mediate diabetic renal injury including lipid and carbohydrate metabolism, inflammation, fibrosis, oxidative stress, and年龄/愤怒。