Regulation of calcium reabsorption along the rat nephron: a modeling study

摘要

We ex-panded a mathematical model of transepithelial transport along the ratnephron to include the transport of Ca2+ and probe the impact ofcalcium-sensing mechanisms on Ca2+ reabsorption. The modelnephron extends from the medullary thick ascending limb (mTAL) tothe inner medullary collecting duct (IMCD). Our model reproducesseveral experimental findings, such as measurements of luminal Ca2+concentrations in cortical tubules, and the effects of furosemide ordeletion of the transient receptor potential channel vanilloid subtype 5(TRPV5) on urinary Ca2+ excretion. In vitro microperfusion of rat TALhas demonstrated that activation of the calcium-sensing receptor CaSRlowers the TAL permeability to Ca2+, Pj'^' (Loupy A, RamakrishnanSK, Wootla B, Chambrey R, de la Faille R, Bourgeois S, Bruneval P,Mandet C, Christensen El, Faure FI, Cheval L, Laghmani K, Collet C,Eladari D, Dodd RH, Ruat M, Houillier P. / Clin Invest 122: 3355,2012). Our results suggest that this regulatory mechanism signifi-cantly impacts renal Ca2+ handling: when plasma Ca2+ concentration([Ca2+]) is raised by 10%, the CaSR-mediated reduction in Pj^1' perse is predicted to enhance urinary Ca2+ excretion by —30%. If high[Ca2+] also induces renal outer medullary potassium (ROMK) inhi-bition, urinary Ca2+ excretion is further raised. In vitro, increases inluminal [Ca2+] have been shown to activate H+-ATPase pumps in theouter medullary CD and to lower the water permeability of IMCD.Our model suggests that if these responses exhibit the sigmoidaldependence on luminal [Ca2+] that is characteristic of CaSR, then theimpact of elevated Ca2+ levels in the CD on urinary volume and pITremains limited. Finally, our model suggests that CaSR inhibitorscould significantly reduce urinary Ca2+ excretion in hypoparathyroid-ism, thereby reducing the risk of calcium stone formation.