Abstract
Calcium (Ca2+) homeostasis is maintained through coordination between intestinal absorption, renal reabsorption, and bone remodeling. Intestinal and renal (re)absorption occurs via transcellular and paracellular pathways. The latter contributes the bulk of (re)absorption under conditions of adequate intake. Epithelial paracellular permeability is conferred by tight-junction proteins called claudins. However, the molecular identity of the paracellular Ca2+ pore remains to be delineated. Claudins (Cldn)-2 and -12 confer Ca2+ permeability, but deletion of either claudin does not result in a negative Ca2+ balance or increased calciotropic hormone levels, suggesting the existence of additional transport pathways or parallel roles for the two claudins. To test this, we generated a Cldn2/12 double knockout mouse (DKO). These animals have reduced intestinal Ca2+ absorption. Colonic Ca2+ permeability is also reduced in DKO mice and significantly lower than single-null animals, while small intestine Ca2+ permeability is unaltered. The DKO mice display significantly greater urinary Ca2+ wasting than Cldn2 null animals. These perturbations lead to hypocalcemia and reduced bone mineral density, which was not observed in single-KO animals. Both claudins were localized to colonic epithelial crypts and renal proximal tubule cells, but they do not physically interact invitro. Overexpression of either claudin increased Ca2+ permeability in cell models with endogenous expression of the other claudin. We find claudin-2 and claudin-12 form partially redundant, independent Ca2+ permeable pores in renal and colonic epithelia that enable paracellular Ca2+ (re)absorption in these segments, with either one sufficient to maintain Ca2+ balance.
Highlights
Calcium (Ca2+) is an essential mineral for physiological processes, including cell signaling, muscle contraction, and bone mineralization
Significant calcium absorption across renal and intestinal epithelia occurs via the paracellular pathway
Employing murine models, detailed balance studies, and ex vivo and in vitro techniques, we provide evidence that either claudin2 or claudin-12 is necessary to maintain Ca2+ homeostasis and optimal bone mineralization
Summary
Calcium (Ca2+) is an essential mineral for physiological processes, including cell signaling, muscle contraction, and bone mineralization. Claudins are membrane proteins with two extracellular loops that interact at the tight junction between cells to form pores for, or barriers to, paracellular movement of solutes by altering the charge and size selectivity characteristics [12] In this manner, claudins confer permeability properties to epithelia. Claudin-2 (Cldn2) knockout (KO) mice have decreased colonic Ca2+ permeability but unaltered small intestine permeability They display decreased fecal Ca2+ excretion (i.e., increased intestinal Ca2+ absorption) and have unaltered bone mineral content and serum Ca2+, relative to wild-type (WT) mice [8, 14]. They display decreased intestinal calcium absorption and renal calcium wasting, resulting in hypocalcemia and markedly reduced bone mineralization. Activation of the Ca2+-sensing receptor by increased plasma Ca2+ increases the expression of the pore blocking claudin, claudin-14, which prevents Ca2+ reabsorption from this segment [18,19,20]
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