Spontaneous tubulointerstital nephritis in kdkd mice

描述(由申请人提供)：具有kd/kd基因的小鼠在出生后的前八周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，该疾病始于白细胞渗透，最终导致终末期肾脏疾病。这种疾病的遗传基础是辅酶Q(CoQ)的异戊二烯基化所需的一种名为Pdss 2的酶的缺陷。当小鼠在饮用水中补充辅酶Q时，对肾脏疾病的显著保护作用就会发生。由于辅酶Q对线粒体呼吸链中的电子传递是必不可少的，也是一种脂溶抗氧化剂，这两种功能中的一种或两种功能的缺陷可能是疾病的基础。当给予突变小鼠普罗布考(一种脂溶抗氧化剂)时，也出现了显著的疾病保护作用，这表明氧化应激是疾病的关键决定因素。肾小球足细胞中不表达Pdss 2的条件性基因敲除概括了kd/kd小鼠的肾脏疾病表型。由于足细胞对能量的需求并不特别高，这也支持了这样的假设，即表型可能是由氧化应激导致的足细胞损伤而不是呼吸链的缺陷造成的。这种疾病在某些方面类似于局灶性节段性肾小球硬化(FSGS)，有证据表明，一些FSGS患者具有相同基因的突变等位基因，但在kd/kd小鼠中存在缺陷。这些假说将通过以下具体目标得到解决：(1)研究治疗Pdss-2相关辅酶Q缺乏症改善肾脏疾病的机制，(2)确定肾脏疾病的表型是由于缺乏亲环素D，还是由于集合管或Henle上行环的Pdss-2缺陷所影响，以及(3)研究PDSS2的不同等位基因在人类FSGS患者中的作用。公共卫生相关性：kd/kd小鼠患有一种类似于FSGS的致命性疾病，由遗传性线粒体缺陷引起，但这种疾病可以通过辅酶Q或普罗布考治疗来预防。可以成功治疗的遗传性线粒体疾病的其他动物模型很少(如果有的话)。因此，这是一个重要的模式，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.