title: Regulation of calcium reabsorption along the rat nephron: a modeling study.
abstract: We expanded a mathematical model of transepithelial transport along the rat nephron to include the transport of Ca(2+) and probe the impact of calcium-sensing mechanisms on Ca(2+) reabsorption. The model nephron extends from the medullary thick ascending limb (mTAL) to the inner medullary collecting duct (IMCD). Our model reproduces several experimental findings, such as measurements of luminal Ca(2+) concentrations in cortical tubules, and the effects of furosemide or deletion of the transient receptor potential channel vanilloid subtype 5 (TRPV5) on urinary Ca(2+) excretion. In vitro microperfusion of rat TAL has demonstrated that activation of the calcium-sensing receptor CaSR lowers the TAL permeability to Ca(2+), PCa (TAL) (Loupy A, Ramakrishnan SK, Wootla B, Chambrey R, de la Faille R, Bourgeois S, Bruneval P, Mandet C, Christensen EI, Faure H, Cheval L, Laghmani K, Collet C, Eladari D, Dodd RH, Ruat M, Houillier P. J Clin Invest 122: 3355, 2012). Our results suggest that this regulatory mechanism significantly impacts renal Ca(2+) handling: when plasma Ca(2+) concentration ([Ca(2+)]) is raised by 10%, the CaSR-mediated reduction in PCa (TAL) per se is predicted to enhance urinary Ca(2+) excretion by ∼30%. If high [Ca(2+)] also induces renal outer medullary potassium (ROMK) inhibition, urinary Ca(2+) excretion is further raised. In vitro, increases in luminal [Ca(2+)] have been shown to activate H(+)-ATPase pumps in the outer medullary CD and to lower the water permeability of IMCD. Our model suggests that if these responses exhibit the sigmoidal dependence on luminal [Ca(2+)] that is characteristic of CaSR, then the impact of elevated Ca(2+) levels in the CD on urinary volume and pH remains limited. Finally, our model suggests that CaSR inhibitors could significantly reduce urinary Ca(2+) excretion in hypoparathyroidism, thereby reducing the risk of calcium stone formation.
authors.affiliation: Sorbonne Universités, Université Pierre et Marie Curie Université Paris 06, Institut National de la Santé et de la Recherche Médicale, Université Paris Descartes, Sorbonne Paris Cité, UMRS 1138, Centre National de la Recherche Scientifique ERL 8228, Centre de Recherche des Cordeliers, Paris, France aurelie.edwards@crc.jussieu.fr.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Edwards
mesh_terms: D000818:Animals; D002118:Calcium / Q000652:urine*; D007684:Kidney Tubules / Q000378:metabolism*; D008954:Models, Biological; D010281:Parathyroid Hormone / Q000502:physiology; D051381:Rats
chemical_list: D010281:Parathyroid Hormone; D002118:Calcium
keywords: CaSR; calcium; epithelium; mathematical model; transport