Spontaneous tubulointerstital nephritis in kdkd mice

描述（由申请人提供）：小管间质性肾炎可能自发发生，但最常在肾功能衰竭过程中的其他病理过程中观察到，并且高度预测终末期疾病。虽然这些病变的特点是单核细胞浸润，但导致浸润的细胞和分子事件尚不完全清楚。具有kd/kd基因型的小鼠具有自发发生的肾脏疾病，其特征是出生时肾脏外观正常，8周时白细胞浸润，此后进展为终末期疾病。这些小鼠在一种戊烯基转移酶样线粒体蛋白（PLMP）的基因上存在缺陷，它们的肾脏和其他组织的线粒体也存在超微结构缺陷。这些缺陷导致自身免疫和炎症的强烈刺激，这可以在没有功能的rag1基因的情况下发生。基于这些发现，我们假设在肾脏线粒体中表达的遗传缺陷使上皮细胞更容易受到细胞损伤和死亡。这进而导致炎症、纤维化和进行性肾衰竭。我们进一步假设，尽管kd/kd纯合子放大了这一系列事件，但可能代表了进行性肾衰竭的一般范例，即遗传决定的损伤反应可能影响疾病进展。这些假设将通过以下具体目的来解决：(1)研究不同细胞和组织对该病发病机制的贡献，(2)研究NK和NKT细胞的作用，并探讨kd/+小鼠发生间质性肾炎的情况，(3)研究kd/kd小鼠的特异性线粒体缺陷。这些研究的结果有可能为导致进行性肾衰竭的事件提供一般的见解，而不依赖于引发疾病的过程。更好地了解这些事件有可能导致人类进行性肾脏疾病患者的新疗法。

DESCRIPTION (provided by applicant): Tubulointerstitial nephritis may occur spontaneously, but it is most often observed in the context of other pathologic processes in the course of renal failure, and it is highly predictive of end stage disease. Although these lesions are characterized by infiltrations of mononuclear cells, the cellular and molecular events leading to the invasion are not fully understood. Mice with the kd/kd genotype have a spontaneously occurring kidney disease, which is characterized by normal appearing kidneys at birth, leukocyte infiltrations at eight weeks, and progression to end stage disease thereafter. These mice have a defect in a gene for a prenyltransferase-like mitochondrial protein (PLMP), and they have ultrastructural defects in the mitochondria of the kidney and other tissues. These defects lead to potent stimulation of autoimmunity and inflammation, and this can occur without a functional Rag-1 gene. Based on these findings, we postulate that the genetic defect expressed in the mitochondria of the kidney renders epithelial cells more susceptible to cell injury and death. This in turn leads to inflammation, fibrosis and progressive renal failure. We further postulate that this sequence of events, although magnified in kd/kd homozygotes, may represent a general paradigm for progressive renal failure, whereby genetically determined responses to injury may influence disease progression. These hypotheses will be addressed through the following specific Aims: (1) to investigate the contributions of different cells and tissues to the pathogenesis of this disease, (2) to investigate the roles of NK and NKT cells, and to explore the circumstances under which kd/+ mice develop interstitial nephritis, and (3) to investigate the specific mitochondrial defect in kd/kd mice. The results of these studies have the potential to provide general insights into the events leading to progressive renal failure, independently of the processes that initiate disease. Developing a better understanding of these events has the potential to lead to novel therapies for human patients with progressive renal disease.