Topala Catalin N, Bindels René J M, Hoenderop Joost G J
Department of Physiology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Curr Opin Nephrol Hypertens. 2007 Jul;16(4):319-24. doi: 10.1097/MNH.0b013e3281c55f02.
Recent studies have greatly increased our knowledge concerning the regulation of renal calcium handling. This review focuses on newly identified calciotropic factors present in the pro-urine and the mechanisms by which they control the transient receptor potential channel vanilloid subtype 5 (TRPV5) which forms the gatekeeper of active renal calcium reabsorption.
The antiaging hormone klotho regulates TRPV5 activity via a novel mechanism modifying its glycosylation status, thereby entrapping the channel at the cell surface. Functional characterization of tissue kallikrein knockout mice revealed that these animals exhibit a pronounced hypercalciuria, comparable to the calcium leak observed in TRPV5 knockout mice. Recently, it has been demonstrated that tissue kallikrein stimulates active calcium reabsorption via the bradykinin receptor type 2 pathway involving protein kinase C-dependent activation of TRPV5. Finally, the extracellular pH appears to act as a dynamic switch controlling cell surface expression of TRPV5.
Unraveling the molecular mechanisms of TRPV5 channel regulation by the antiaging hormone klotho, tissue kallikrein and extracellular pH demonstrated the existence of novel regulatory mechanisms of active calcium reabsorption acting from the tubular lumen.
近期研究极大地增加了我们对肾钙处理调节的认识。本综述聚焦于原尿中新发现的钙调节因子，以及它们控制瞬时受体电位香草酸亚型5（TRPV5）的机制，TRPV5是肾脏主动钙重吸收的守门人。
抗衰老激素klotho通过一种改变其糖基化状态的新机制调节TRPV5活性，从而将该通道截留在细胞表面。组织激肽释放酶基因敲除小鼠的功能特征显示，这些动物表现出明显的高钙尿症，与TRPV5基因敲除小鼠中观察到的钙泄漏相当。最近，已证明组织激肽释放酶通过涉及蛋白激酶C依赖性激活TRPV5的2型缓激肽受体途径刺激主动钙重吸收。最后，细胞外pH似乎作为一个动态开关控制TRPV5的细胞表面表达。
揭示抗衰老激素klotho、组织激肽释放酶和细胞外pH对TRPV5通道的调节分子机制，证明了存在从肾小管腔起作用的主动钙重吸收新调节机制。
