Abstract：
Dent disease (DD) is a hereditary renal disorder characterized by low molecular weight (LMW) proteinuria and progressive renal failure. Inactivating mutations of the CLCN5 gene encoding the 2Cl-/H+exchanger ClC-5 have been identified in patients with DD type 1. ClC-5 is essentially expressed in proximal tubules (PT) where it is thought to play a role in maintaining an efficient endocytosis of LMW proteins. However, the exact pathological roles of ClC-5 in progressive dysfunctions observed in DD type 1 are still unclear. To address this issue, we designed a mouse model carrying the most representative type of ClC-5 missense mutations found in DD patients. These mice showed a characteristic DD type 1 phenotype accompanied by altered endo-lysosomal system and autophagy functions. With ageing, KI mice showed increased renal fibrosis, apoptosis and major changes in cell metabolic functions as already suggested in previous DD models. Furthermore, we made the interesting new discovery that the Lipocalin-2-24p3R pathway might be involved in the progression of the disease. These results suggest a crosstalk between the proximal and distal nephron in the pathogenesis mechanisms involved in DD with an initial PT impairment followed by the Lipocalin-2 internalisation and 24p3R overexpression in more distal segments of the nephron. This first animal model of DD carrying a pathogenic mutation of Clcn5 and our findings pave the way aimed at exploring therapeutic strategies to limit the consequences of ClC-5 disruption in patients with DD type 1 developing chronic kidney disease.
摘要：
Dent病（DD）是一种遗传性肾脏疾病，其特征是低分子量（LMW）蛋白尿和进行性肾功能衰竭。已在1型DD患者中鉴定出编码2Cl-/H交换子ClC-5的CLCN5基因的失活突变。ClC-5基本上在近端小管(PT)中表达,认为其在维持LMW蛋白的有效胞吞中起作用。然而,ClC-5在DD1型进行性功能障碍中的确切病理作用尚不清楚.为了解决这个问题，我们设计了一个小鼠模型,该模型携带在DD患者中发现的最具代表性的ClC-5错义突变类型.这些小鼠表现出特征性的DD1型表型，伴有内溶酶体系统和自噬功能的改变。随着老龄化,KI小鼠肾纤维化增加，细胞凋亡和细胞代谢功能的主要变化已经在以前的DD模型中提出。此外，我们发现了一个有趣的新发现，即Lipocalin-2-24p3R通路可能参与了疾病的进展。这些结果表明，在DD涉及的发病机制中，近端和远端肾单位之间存在串扰，最初的PT受损，随后是脂质运载蛋白2内在化和24p3R在肾单位的更远端部分过表达。第一个携带Clcn5致病性突变的DD动物模型和我们的发现为寻找治疗策略以限制1型DD发展为慢性肾脏疾病的患者中ClC-5破坏的后果铺平了道路。
