Spontaneous tubulointerstital nephritis in kdkd mice

描述（由申请人提供）：具有kd/kd基因型的小鼠在生命的前八周具有明显的正常健康状态，但随后发展为自发发生的肾脏疾病，从白细胞浸润开始，最终导致终末期肾脏疾病。这种疾病的遗传基础是一种被称为Pdss2的酶的缺陷，它是辅酶Q （CoQ）异戊二烯化所必需的。当小鼠在饮用水中补充CoQ时，对肾脏疾病有显著的保护作用。由于辅酶q对线粒体呼吸链中的电子转移至关重要，并且还作为脂溶性抗氧化剂，因此这些功能中的任何一个或两个缺陷都可能是该疾病的基础。当突变小鼠被给予Probucol（一种脂溶性抗氧化剂）时，也发生了显著的疾病保护，这表明氧化应激是疾病的关键决定因素。在肾小球足细胞中不表达Pdss2的条件敲除重现了kd/kd小鼠的肾脏疾病表型。由于不知道足细胞有特别高的能量需求，这也支持了这种表型可能是由氧化应激引起的足细胞损伤而不是呼吸链缺陷引起的假设。这种疾病在某些方面与局灶节段性肾小球硬化（FSGS）相似，有证据表明，一些FSGS患者具有kd/kd小鼠中存在缺陷的同一基因的突变等位基因。这些假设将通过以下具体目的来解决：(1)研究Pdss2相关的CoQ缺乏症治疗改善肾脏疾病的机制；(2)确定肾脏疾病的表型是否受到亲环蛋白D缺失的影响，还是受集管或Henle上升袢中Pdss2缺乏症的影响；(3)研究Pdss2变异等位基因在人类FSGS患者中的作用。公共卫生相关性：kd/kd小鼠有一种由遗传性线粒体缺陷引起的类似FSGS的致死性疾病，但这种疾病可以通过CoQ或Probucol治疗来预防。即使有，也很少有其他遗传性线粒体疾病的动物模型可以成功治疗。因此，这是一个重要的模型，有可能帮助开发治疗患有类似疾病的人类的疗法。

DESCRIPTION (provided by applicant): Mice with the kd/kd genotype have an apparently normal state of health for the first eight weeks of life, but then develop a spontaneously occurring kidney disease which begins with leukocyte infiltrations and eventually leads to end stage renal disease. The genetic basis for this disease is a defect in an enzyme, designated Pdss2, that is needed for the isoprenylation of coenzyme Q (CoQ). Significant protection from renal disease occurs when the mice are given supplemental CoQ in the drinking water. As CoQ is essential for electron transfer in the mitochondrial respiratory chain and also serves as a lipid-soluble antioxidant, a defect in either or both of these functions could be the basis for the disease. When mutant mice were given Probucol, which is a lipid-soluble antioxidant, significant protection against disease also occurred, which suggests that oxidative stress is the critical determinant of disease. Conditional knockouts that do not express Pdss2 in the glomerular podocytes recapitulate the kidney disease phenotype of kd/kd mice. As the podocyte is not known to have an especially high energetic requirement, this also supports the hypothesis that the phenotype may result from podocyte damage caused by oxidative stress rather than a deficiency in the respiratory chain. This disease is similar in certain respects to focal segmental glomerulosclerosis (FSGS), and there is evidence that some patients with FSGS have mutant alleles of the same gene that is defective in kd/kd mice. These hypotheses will be addressed through the following specific aims: (1) To investigate the mechanisms by which therapy of Pdss2-related CoQ deficiency ameliorates renal disease, (2) To determine whether the kidney disease phenotype is affected by an absence of cyclophilin D, or by Pdss2 deficiencies in the collecting duct or ascending loop of Henle, and (3) To investigate the effects of variant alleles of PDSS2 in human patients with FSGS. PUBLIC HEALTH RELEVANCE: The kd/kd mouse has a lethal disease similar to FSGS caused by an inherited mitochondrial defect, but this disease can be prevented by treatment with CoQ or Probucol. There are very few, if any, other animal models of an inherited mitochondrial disease that can be successfully treated. This is therefore an important model, with the potential for helping to develop therapies for humans with similar disorders.