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.

A model of calcium homeostasis in the rat

“…It has been suggested that CaSR inhibitors may be used to treat disorders related to impaired PTH secretion (61), and a recent model of Ca 2ϩ transport along the nephron suggests that blocking the renal CaSR could significantly reduce urinary Ca 2ϩ excretion in the absence of PTH secretion (32). In the present study, fractional Ca 2ϩ reabsorption along the entire nephron equals 88.2% in parathyroidectomized rats.…”

“…Finally, the model is hampered by its description of organs as black boxes, meaning that transport and regulation mechanisms at the molecular and cellular scales are described instead by simplified relationships, such as first-order kinetics and Michaelis-Menten equations. There exists detailed, cellularbased models of calcium homeostasis in kidney (32), and intestine (33,46,83); these could be integrated in the present mathematical model in the future. Similarly, models of bone remodeling could be incorporated to describe more accurately the dynamics of bone resorption and formation (58,71).…”

“…Inhibition of the renal CaSR would raise that fraction to 92.4%, without a noticeable impact on [Ca 2ϩ ] p or on calcium exchanges between other compartments. However, given that concentration of Ca 2ϩ in the tubular fluid increases ϳ10-fold along the collecting duct, a small increase in reabsorption in the TAL can have a significant impact on urinary concentration (32 We investigated the effects of bisphosphonates on calcium metabolism in rats by lowering the maximal resorption rate over the entire duration of the simulation. Thus our results should be compared with experimental studies in which bisphosphonates were administered to rats chronically.…”

Predicted consequences of diabetes and SGLT inhibition on transport and oxygen consumption along a rat nephron

“…The model is based on previously applied models of the proximal tubule (26), TAL (12), distal convoluted tubule (DCT) (11), connecting tubule (CNT) (11), and collecting duct (CD) (53), together with a new, simple model of the descending limb (see below). Each nephron segment is represented as a rigid tubule lined by a layer of epithelial cells, with apical and basolateral transporters that vary according to cell type (Fig.…”

Claudins in Renal Physiology and Pathology

“…Those concentrations have been reported in mathematical models except for magnesium (*). Estimates of the luminal and interstitial concentrations of Na + , Cl − and Ca 2+ in the early medullary thick ascending limbs have been published in mathematical models [120][121][122][123][124][125][126].…”