Regulation of renal calcium transport

描述（由申请人提供）：肾脏对维持钙稳态至关重要。大部分在肾小球滤过的钙离子（Ca2+）必须通过细胞旁和细胞外两种途径被小管重新吸收。发生在远端肾小管的跨细胞Ca2+重吸收约占总重吸收的10-20%，被认为是激素（如甲状旁腺激素）和酸碱状态调节钙稳态的主要目标。瞬时受体电位型V5 （TRPV5）通道定位于远端肾小管顶端膜是肾脏跨细胞Ca2+重吸收的守门人。我们研究的总体长期目标是了解与肾钙转运紊乱相关的生理和病变状态下TRPV5调控的分子机制。为此，我们将探讨当前提案中的以下3个目标。目的1将探讨pH和Mg2+调节TRPV5的机制和相互关系。目的2将探讨甲状旁腺激素（PTH）调控TRPV5的机制。目的3将研究抗衰老激素Klotho在TRPV5调控中的分子机制。我们将使用互补的生化，电生理和动物方法的组合。这些研究与肾结石直接相关，因为Mg2+和碱已被用于治疗肾结石疾病，尿Mg2+和尿pH的改变会影响尿Ca2+。甲状旁腺激素是一种主要的降钙激素，但甲状旁腺激素调节肾脏Ca2+再吸收的机制仍然难以捉摸。对Klotho的研究将阐明我们对Klotho如何在不引起骨骼问题的情况下降低血清磷（长寿的重要因素）的理解。尿Ca2+浓度是肾结石疾病的关键决定因素。这些研究将极大地促进对TRPV5生物学和分子调控的认识。这一建议的结果可能会提高对结石形成和治疗过程的理解。

DESCRIPTION (provided by applicant): The kidney is critical for maintaining calcium homeostasis. Most of the calcium ion (Ca2+) filtered at the glomerulus must be reabsorbed by tubules through both paracellular and transcellular pathways. The transcellular Ca2+ reabsorption occurring in the distal renal tubules accounts for ~10-20% of total reabsorption and is believed to be the primary target for regulation of calcium homeostasis by hormones (such as parathyroid hormone) and acid-base status. Transient receptor potential type V5 (TRPV5) channel localized to the apical membrane of distal renal tubules is a gatekeeper for transcellular Ca2+ reabsorption in the kidney. The overall long- term goal of our research is to understand the molecular mechanisms of regulation of TRPV5 in physiological and diseased states associated with disturbances of renal calcium transport. To this end, we will investigate the following 3 aims in the current proposal. Aim 1 will examine the mechanism and interrelationship between pH and Mg2+ regulation of TRPV5. Aim 2 will examine the mechanism of regulation of TRPV5 by parathyroid hormone (PTH). Aim 3 will examine the molecular mechanism of Klotho, an anti-aging hormone, in the regulation of TRPV5. We will use a combination of complementary biochemical, electrophysiological, and animal approaches. These studies are directly relevant to nephrolithiasis, since Mg2+ and alkali have been used in the treatment of kidney stone disease, and alterations in urinary Mg2+ and urinary pH influence urinary Ca2+. PTH is a principal calcitropic hormone but the mechanism by which PTH regulates renal Ca2+ reabsorption remains largely elusive. The study of Klotho will shed lights on our understanding of how Klotho can lower serum phosphorus (an important factor for longevity of life) without causing bone problems. Urinary Ca2+ concontration is critical determinant of kidney stone diseases. These studies will greatly advance understanding of TRPV5 biology and molecular regulation. Results of this proposal may provide improved undestanding of the process of stone formation and of treatment. PUBLIC HEALTH RELEVANCE: Kidney stone disease is very common. About 20% of adults suffer from kidney stone disease at least once in their life time. Increase in urinary calcium excretion is a major cause for kidney stone formation. Our studies will help to understand why calcium stone forms and to design treatment for the disease.