Granjon David, Bonny Olivier, Edwards Aurélie
Sorbonne Universités, UPMC Univ Paris 06, Université Paris Descartes, Sorbonne Paris Cité, INSERM UMRS 1138, CNRS ERL 8228, Centre de Recherche des Cordeliers, Paris, France; and.
Department of Pharmacology and Toxicology, University of Lausanne, and Service of Nephrology, Lausanne University Hospital, Lausanne, Switzerland.
Am J Physiol Renal Physiol. 2016 Nov 1;311(5):F1047-F1062. doi: 10.1152/ajprenal.00230.2016. Epub 2016 Jun 29.
We developed a model of calcium homeostasis in the rat to better understand the impact of dysfunctions such as primary hyperparathyroidism and vitamin D deficiency on calcium balance. The model accounts for the regulation of calcium intestinal uptake, bone resorption, and renal reabsorption by parathyroid hormone (PTH), vitamin D, and Ca itself. It is the first such model to incorporate recent findings regarding the role of the calcium-sensing receptor (CaSR) in the kidney, the presence of a rapidly exchangeable pool in bone, and the delayed response of vitamin D synthesis. Accounting for two (fast and slow) calcium storage compartments in bone allows the model to properly predict the effects of bisphophonates on the plasma levels of Ca ([Ca]), PTH, and vitamin D Our model also suggests that Ca exchange rates between plasma and the fast pool vary with both sex and age, allowing [Ca] to remain constant in spite of sex- and age-based hormonal and other differences. Our results suggest that the inconstant hypercalciuria that is observed in primary hyperparathyroidism can be attributed in part to counterbalancing effects of PTH and CaSR in the kidney. Our model also correctly predicts that calcimimetic agents such as cinacalcet bring down [Ca] to within its normal range in primary hyperparathyroidism. In addition, the model provides a simulation of CYP24A1 inactivation that leads to a situation reminiscent of infantile hypercalcemia. In summary, our model of calcium handling can be used to decipher the complex regulation of calcium homeostasis.
我们建立了大鼠钙稳态模型，以更好地理解原发性甲状旁腺功能亢进和维生素D缺乏等功能障碍对钙平衡的影响。该模型考虑了甲状旁腺激素（PTH）、维生素D和钙本身对钙肠道吸收、骨吸收和肾重吸收的调节作用。它是首个纳入有关肾中钙敏感受体（CaSR）作用、骨中快速交换池的存在以及维生素D合成延迟反应等最新研究结果的此类模型。考虑到骨中的两个（快速和缓慢）钙储存隔室，该模型能够正确预测双膦酸盐对血浆钙水平（[Ca]）、PTH和维生素D的影响。我们的模型还表明，血浆与快速池之间的钙交换率随性别和年龄而变化，尽管存在基于性别和年龄的激素及其他差异，但仍能使[Ca]保持恒定。我们的结果表明，原发性甲状旁腺功能亢进中观察到的不稳定高钙尿症部分可归因于肾脏中PTH和CaSR的平衡作用。我们的模型还正确预测，西那卡塞等拟钙剂可使原发性甲状旁腺功能亢进中的[Ca]降至正常范围内。此外，该模型模拟了CYP24A1失活，导致出现类似于婴儿高钙血症的情况。总之，我们的钙处理模型可用于解读钙稳态的复杂调节机制。
