Spontaneous tubulointerstital nephritis in kdkd mice

描述(申请人提供)：肾小管间质肾炎可以自发发生，但最常在肾功能衰竭过程中的其他病理过程中观察到，它对终末期疾病有很高的预测性。虽然这些病变的特点是单个核细胞的浸润性，但导致侵袭的细胞和分子事件尚不完全清楚。具有kd/kd基因的小鼠有一种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。这些小鼠的异丙苯基转移酶类线粒体蛋白(PLMP)的基因存在缺陷，它们的肾脏和其他组织的线粒体存在超微结构缺陷。这些缺陷导致对自身免疫和炎症的强烈刺激，而这可能在没有功能RAG-1基因的情况下发生。根据这些发现，我们推测肾脏线粒体中表达的基因缺陷使上皮细胞更容易受到细胞损伤和死亡的影响。这反过来会导致炎症、纤维化和进行性肾功能衰竭。我们进一步推测，尽管这一系列事件在kd/kd纯合子中被放大，但它可能代表了进行性肾功能衰竭的一般范例，由此对损伤的基因决定的反应可能影响疾病的进展。这些假说将通过以下特定目的来解决：(1)研究不同细胞和组织在本病发病机制中的作用；(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小鼠特有的线粒体缺陷。这些研究的结果有可能为导致进展性肾功能衰竭的事件提供一般性的见解，独立于引发疾病的过程。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.