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标题：Claudin-2 and claudin-12 form independent, complementary pores required to maintain calcium homeostasis
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作者：Megan R. Beggs ; Kennedi Young ; Wanling Pan 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2021
卷号：118
期号：48
DOI：10.1073/pnas.2111247118
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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 Ca 2+ pathway in intestine and kidney enabling calcium transport and highlights their important complementary roles in maintaining calcium homeostasis. Calcium (Ca 2+) 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 Ca 2+ pore remains to be delineated. Claudins ( Cldn)-2 and -12 confer Ca 2+ permeability, but deletion of either claudin does not result in a negative Ca 2+ 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 Ca 2+ absorption. Colonic Ca 2+ permeability is also reduced in DKO mice and significantly lower than single-null animals, while small intestine Ca 2+ permeability is unaltered. The DKO mice display significantly greater urinary Ca 2+ 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 Ca 2+ permeability in cell models with endogenous expression of the other claudin. We find claudin-2 and claudin-12 form partially redundant, independent Ca 2+ permeable pores in renal and colonic epithelia that enable paracellular Ca 2+ (re)absorption in these segments, with either one sufficient to maintain Ca 2+ balance.
关键词：claudins; calcium; paracellular