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8周内具有明显正常的健康状态，但随后发展为自发发生的肾病，其开始于白细胞浸润并最终导致终末期肾病。这种疾病的遗传基础是一种称为Pdss 2的酶的缺陷，这种酶是辅酶Q（CoQ）异戊二烯化所必需的。当在饮用水中给予小鼠补充辅酶Q时，发生了对肾脏疾病的显着保护。由于辅酶Q对线粒体呼吸链中的电子转移至关重要，并且还充当脂溶性抗氧化剂，因此这些功能中的一个或两个的缺陷可能是疾病的基础。当突变小鼠被给予普罗布考（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Pdss 2的条件性敲除概括了kd/kd小鼠的肾病表型。由于不知道足细胞具有特别高的能量需求，这也支持了这样的假设，即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。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患者具有与kd/kd小鼠中缺陷相同基因的突变等位基因。这些假设将通过以下具体目标加以解决：（1）研究Pdss 2相关的辅酶Q缺乏症的治疗改善肾脏疾病的机制，（2）确定肾脏疾病表型是否受到亲环素D缺乏的影响，或受到集合管或Henle上行袢中Pdss 2缺乏的影响，（3）研究PDSS 2基因多态性在FSGS患者中的作用。公共卫生相关性：kd/kd小鼠具有由遗传性线粒体缺陷引起的类似于FSGS的致死性疾病，但这种疾病可以通过CoQ或Probucol治疗来预防。很少有（如果有的话）可以成功治疗遗传性线粒体疾病的其他动物模型。因此，这是一个重要的模型，有可能帮助开发治疗类似疾病的人类。

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.