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Investigation of Genetic and Molecular Basis of Diabetic Nephropathy Susceptibility in Mice.

机译：小鼠糖尿病肾病易感性的遗传和分子基础研究。

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摘要

Diabetic nephropathy (DN) is one of the major causes of morbidity and mortality in diabetic patients and also the leading single cause of end stage renal disease (ESRD) in the United States. However, approximately 40% of diabetic patients develop DN, demonstrating a significant genetic component of disease susceptibility and progression. Differential susceptibilities to DN have also been observed between well-defined strains of inbred rodents. For example, DBA/2J mice represent a susceptible, while C57BL/6J mice demonstrate a resistant genetic background to the development of DN. However, in both humans and animal models, the molecular and genetic mechanisms underlying DN susceptibility have not been fully elucidated.;In kidney diseases, progressive loss of filtration and glomerulosclerosis are typically associated with permanent podocyte injury/depletion and expansion of mesangial matrix with mesangial hypertrophy. In this study, we determined that DBA/2J inbred strain manifest podocyte loss in response to diabetes induced by either streptozotocin injection or Insulin2 Akita genetic mutations, while C57BL/6J strain was protected from podocyte loss. When compared with non-diabetic controls, podocyte number per glomerular section area decreased by 27% in diabetic DBA/2J mice, but no reduction of podocytes was observed in diabetic C57BL/6J mice. Thus we demonstrated that DBA/2J strain is susceptible and C57BL/6J is resistant to diabetes-induced podocyte depletion and that actually goes along with the susceptibility to diabetic nephropathy.;In order to characterize glomerular transcriptome profiles associated with differential susceptibility to glomerular manifestations of DN in diabetic DBA/2J mice in comparison with diabetic C57BL/6J mice, glomerular microarray analysis was performed and glomerular transcriptomic profiles were compared between diabetic and non-diabetic mice. Based on pathway analysis of expression profiles, mitochondrial dysfunction and impaired oxidative phosphorylation were characteristic glomerular trancriptome profiles in DN-susceptible diabetic DBA/2J mice, compared with DN-resistant diabetic C57BL/6J mice. These computational predictions were confirmed by functional tests (mitochondrial oxygen consumption rate tests and anti-8 oxoG staining), demonstrating that glomerular mitochondrial dysfunction and oxidative damage were detectable already during initial stages of diabetes in DBA/2J mice, but not in C57BL/6J mice.;To investigate the genetic basis of DN susceptibility, we used the BXD recombinant inbred panel to map genetic loci (QTL) associated with number of podocytes after long-term diabetes (6 months of diabetes). We identified two suggestive QTLs on chromosome 13 (LDPD1) and 17 (LDPD2) influencing the number of podocytes in diabetic mice, in which 32 genes reside. In an effort to determine candidate gene(s) underlying these two QTLs, we utilized extensive available information regarding sequence variants (SNPs) and differential expression of these genes in the C57BL/6J and DBA/2J parental strains, as well as the functional pathway activity and the information of cis-acting expression regulatory QTL mapping of these genes. Based on above criteria, xanthine dehydrogenase (Xdh) was prioritized as the candidate gene, contributing to podocyte reduction and DN susceptibility of DBA/2J mice.;Xdh gene was localized under the peak of the LDPD2 QTL on Chromosome 17. Xdh expression was strongly increased by diabetes in glomeruli of DBA/2J, but not C57BL/6J mice. Xdh and xanthine oxidase (XO) are interconvertible forms of the same enzyme encoded by the Xdh gene. XO is known to produce ROS. To validate a functional role of XO contribution to podocyte depletion and DN, we subjected diabetic DBA/2J mice to XO inhibitor, and found significant amelioration of DN, including reduced albuminuria and podocyte loss in diabetic mice. In addition, protein oxidation damage in the glomeruli of diabetic mice was also reduced by the XO inhibitor treatment. as shown by anti-3 nitrotyrosine staining. Thus, we have identified XDH/XO as a critical player in the DN of DBA/2J mice, probably through altering ROS generation in the glomeruli.
机译：糖尿病肾病（DN）是糖尿病患者发病和死亡的主要原因之一，也是美国终末期肾病（ESRD）的主要单一原因。但是，大约40％的糖尿病患者会出现DN，这表明疾病易感性和进展的重要遗传因素。在明确定义的近交啮齿动物品系之间，也观察到对DN的敏感性差异。例如，DBA / 2J小鼠代表易感人群，而C57BL / 6J小鼠表现出对DN产生抗性的遗传背景。然而，在人类和动物模型中，尚未完全阐明DN易感性的分子和遗传机制。在肾脏疾病中，进行性滤失和肾小球硬化的逐步丧失通常与永久性足细胞损伤/耗竭以及肾小球系膜基质的扩张有关肥大。在这项研究中，我们确定DBA / 2J近交菌株对链脲佐菌素注射液或Insulin2秋田遗传突变诱导的糖尿病表现出足细胞损失，而C57BL / 6J菌株受到保护，免受足细胞损失。与非糖尿病对照组相比，糖尿病DBA / 2J小鼠每肾小球截面积的足细胞数量减少了27％，但在糖尿病C57BL / 6J小鼠中未观察到足细胞的减少。因此，我们证明了DBA / 2J菌株易感，而C57BL / 6J对糖尿病引起的足细胞耗竭具有抵抗力，并且实际上与糖尿病性肾病的易感性同时发生。；为了表征与不同的易感性肾小球表现相关的肾小球转录组谱与糖尿病C57BL / 6J小鼠相比，糖尿病DBA / 2J小鼠的DN进行了肾小球微阵列分析，并比较了糖尿病和非糖尿病小鼠的肾小球转录组谱。根据表达谱的通路分析，与DN耐药的糖尿病C57BL / 6J小鼠相比，DN敏感的糖尿病DBA / 2J小鼠的特征性肾小球转录组谱是线粒体功能障碍和氧化磷酸化受损。这些计算预测已通过功能测试（线粒体耗氧率测试和抗8 oxoG染色）得到证实，表明在糖尿病的初始阶段已经在DBA / 2J小鼠中检测到了肾小球线粒体功能障碍和氧化损伤，但在C57BL / 6J小鼠中未检测到为了研究DN易感性的遗传基础，我们使用了BXD重组近交组来绘制与长期糖尿病（6个月糖尿病）后足细胞数量相关的遗传位点（QTL）。我们在第13号染色体（LDPD1）和第17号（LDPD2）上鉴定了两个暗示性QTL，这些QTL影响糖尿病小鼠的足细胞数量，其中存在32个基因。为了确定这两个QTL的候选基因，我们利用了有关C57BL / 6J和DBA / 2J亲本菌株中这些基因的序列变异（SNP）和差异表达的广泛可用信息，以及功能途径活性和这些基因的顺式作用调节QTL定位信息。根据上述标准，黄嘌呤脱氢酶（Xdh）被优先用作候选基因，有助于减少DBA / 2J小鼠的足细胞和DN敏感性。Xdh基因位于染色体17上的LDPD2 QTL峰下。糖尿病会使DBA / 2J的肾小球增加，但C57BL / 6J的小鼠没有。 Xdh和黄嘌呤氧化酶（XO）是Xdh基因编码的同一酶的可相互转换形式。已知XO会产生ROS。为了验证XO对足细胞耗竭和DN的功能作用，我们对糖尿病DBA / 2J小鼠进行了XO抑制剂治疗，发现DN的显着改善，包括糖尿病小鼠白蛋白尿减少和足细胞丢失。另外，通过XO抑制剂处理还减少了糖尿病小鼠肾小球中蛋白质氧化损伤。如抗3硝基酪氨酸染色所示。因此，我们已经确定XDH / XO是DBA / 2J小鼠DN中的关键角色，可能是通过改变肾小球中的ROS产生。

著录项

  • 作者

    Qi, Haiying.;

  • 作者单位

    Mount Sinai School of Medicine.;

  • 授予单位 Mount Sinai School of Medicine.;
  • 学科 Biology Molecular.;Biology Genetics.;Health Sciences Medicine and Surgery.
  • 学位 Ph.D.
  • 年度 2011
  • 页码 170 p.
  • 总页数 170
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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