TRP channels as therapeutic targets in kidney disease and hypertension.
TRP channels as therapeutic targets in kidney disease and hypertension.
复制标题
DOI：
10.2174/1568026611313030013
复制
发表时间：
2013-01
影响因子：
3.4
通讯作者：
P. Menè;G. Punzo;N. Pirozzi
中科院分区：
文献类型：
--
作者：
P. Menè;G. Punzo;N. Pirozzi
果蝇trp同源物瞬时受体电位（TRP）阳离子通道在大多数物种和细胞类型中普遍存在。功能性TRP亚类TRPC、TRPV和TRPP门控哺乳动物组织（包括肾脏）中的Ca 2+和其它阳离子。现在很清楚，TRP通道在肾脏生理学和某些肾脏遗传疾病中起着重要作用。因此，人们对靶向突变或功能障碍的TRP通道以治疗此类疾病有相当大的兴趣。跨细胞上皮细胞Ca 2+重吸收通过管腔TRPV 5/V6通道发生在远端小管中。事实上，TRPV 5 KO小鼠表现出肾脏疾病的表型缺陷，包括高钙尿症和骨矿物质密度受损。与Ca 2+类似，Mg 2+跨细胞重吸收通过顶端TRPM 6/TRPM 7通道发生在远曲小管中。TRPC 6是肾小球足细胞“狭缝隔膜”的组成部分，其常染色体显性突变与家族性、类固醇耐药形式的肾病综合征有关。一种更常见的遗传性肾小管上皮疾病，常染色体显性多囊肾病（ADPKD），至少部分与多囊蛋白2（PC 2）突变有关，PC 2是PKD 2基因编码的一种蛋白质。PC 2现在被鉴定为TRPP 2，一种位于肾小管上皮细胞纤毛上的Ca（2+）渗透性非选择性阳离子通道。TRP相关的离子转运也可能通过调节血管平滑肌收缩、肾灌注/血流动力学以及二价阳离子的全身平衡在动脉全身性和/或肺动脉高压的发病机制中发挥作用。因此，多个肾脏TRP通道是旨在预防或减轻慢性肾脏疾病负担的药物干预的潜在靶点。
The Drosophila trp homologue Transient Receptor Potential (TRP) cation channels are ubiquitous in most species and cell types. The functional TRP subclasses TRPC, TRPV and TRPP gate Ca2+ and other cations in mammalian tissues, including the kidney. It is now clear that TRP channels play an important role in renal physiology and in certain genetic disorders of the kidney. Hence, there is considerable interest in targeting mutated or dysfunctional TRP channels in an effort to treat such diseases. Transcellular epithelial cell Ca2+ reabsorption occurs in the distal tubule via luminal TRPV5/V6 channels. Indeed, TRPV5 KO mice display phenotypic defects of renal disease, including hypercalciuria and impaired bone mineral density. Similar to Ca2+, Mg2+ transcellular reabsorption occurs in the distal convoluted tubule via apical TRPM6/TRPM7 channels. TRPC6 is a component of the glomerular podocyte "slit diaphragm" and its autosomic dominant mutation has been linked to a familial, steroid-resistant form of nephrotic syndrome. A more common inherited disorder of the tubular epithelium, autosomal dominant polycystic kidney disease (ADPKD), is at least in part related to mutation of polycystin 2 (PC2), a protein encoded by the PKD2 gene. PC2 is now identified as TRPP2, a Ca(2+)-permeable non-selective cation channel located on the cilia of tubular epithelial cells. TRP-related ion transport may also play a role in the pathogenesis of arterial systemic and/or pulmonary hypertension through regulation of vascular smooth muscle contraction, renal perfusion/hemodynamics, as well as the total body balance of divalent cations. Thus, multiple renal TRP channels are potential targets for pharmacological intervention aimed at preventing or attenuating the burden of chronic kidney disease.