Claudin-2 and claudin-12 form independent, complementary pores required to maintain calcium homeostasis

Autor: Wanling Pan, Debbie O'Neill, Kennedi Young, Allein Plain, Juraj Rievaj, Matthew Saurette, R. Todd Alexander, Emmanuelle Cordat, Megan R Beggs, Michael R. Doschak, Henrik Dimke
Rok vydání: 2021
Předmět:
Zdroj: Beggs, M R, Young, K, Pan, W, O'Neill, D D, Saurette, M, Plain, A, Rievaj, J, Doschak, M R, Cordat, E, Dimke, H & Alexander, R T 2021, ' Claudin-2 and claudin-12 form independent, complementary pores required to maintain calcium homeostasis ', Proceedings of the National Academy of Sciences of the United States of America, vol. 118, no. 48, e2111247118 . https://doi.org/10.1073/pnas.2111247118
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
0027-8424
Popis: Significance Significant calcium absorption across renal and intestinal epithelia occurs via the paracellular pathway. However, the identity of the paracellular pore involved is unknown. Claudin-2 and claudin-12 contribute paracellular calcium permeability in cell models, but single knockout animals don’t have altered serum calcium or bone mineralization. To investigate this, Cldn2/12 double knockout mice were generated. They display decreased intestinal calcium absorption and renal calcium wasting, resulting in hypocalcemia and markedly reduced bone mineralization. Claudin-2 and claudin-12 don’t physically interact in vitro, and coexpression has an additive effect on calcium permeability. Our work identifies claudin-2 and claudin-12 as important constituents of the paracellular Ca2+ pathway in intestine and kidney enabling calcium transport and highlights their important complementary roles in maintaining calcium homeostasis.
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 in vitro. 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.
Databáze: OpenAIRE
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