Spontaneous tubulointerstital nephritis in kdkd mice

项目摘要 具有kd/kd基因的小鼠第一次有一个明显正常的健康状态。 八周的生命，但随后患上了一种自发发生的肾脏疾病 从白细胞渗入开始，最终导致终末期肾病。这个 这种疾病的遗传基础是一种名为Pdss 2的酶的缺陷，这种酶是必需的 用于辅酶Q(CoQ)的异戊二烯基化。对肾脏疾病的显著保护 当小鼠在饮用水中补充辅酶Q时发生。就像Coq一样 对线粒体呼吸链中的电子传递是必不可少的，也是 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基础 治疗这种疾病。当突变小鼠被给予普罗布考时，普罗布考是一种脂溶的 抗氧化剂，对疾病也有显著的保护作用，这表明 氧化应激是疾病的关键决定因素。有条件的淘汰赛 肾小球足细胞中Pdss-2的表达可概括肾小球疾病表型 KD/kd小鼠。因为足细胞并不具有特别高的能量 要求，这也支持表型可能源于 足细胞损伤是由氧化应激引起的，而不是呼吸系统的缺陷 链条。这种疾病在某些方面类似于局灶节段性肾小球硬化。 (FSGS)，而且有证据表明，一些FSGS患者具有突变的等位基因 同样的基因在kd/kd小鼠中是有缺陷的。这些假设将通过 具体目的如下：(1)探讨脑出血的治疗机制。 Pdss 2相关辅酶Q缺乏改善肾脏疾病，(2)确定 肾脏疾病表型受亲环素D缺失或Pdss 2的影响 Henle的集合管或上行环的缺陷，以及(3)研究 PDSS2等位基因变异对FSGS患者的影响

Project Summary 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.