Role of intestinal claudin-2 in calcium permeability and whole body calcium balance

Kidney stone disease is characterized by hypercalciuria and intestinal hyperabsorption of calcium, leading to the formation of calcium crystals in the kidney. Claudin-2 is a tight junction protein that forms paracellular cation pores, and mutations in its gene are associated with kidney stone disease. We have recently shown that mice deficient in <i>Cldn2</i> are hypercalciuric due to both decreased renal reabsorption and increased intestinal absorption of calcium and develop medullary mineral deposits reminiscent of kidney stone formers. Therefore, we hypothesized that intestinal claudin-2 is important for calcium secretion and that loss of claudin-2 results in increased net intestinal calcium absorption, thereby contributing to kidney stone disease. To test this, we generated intestine-specific <i>Cldn2</i> knockout mice using a villin-Cre promoter. Female mice showed <i>Cldn2</i> deletion only in the intestine; however, male mice showed partial deletion of <i>Cldn2</i> in kidneys. Ileal and colonic calcium permeability were significantly reduced in knockout animals of both sexes. Knockout animals developed transient hypercalciuria (more severe in males than females) at weaning, which was normalized by 4 wk of age. In metabolic balance studies, there was no change in net calcium absorption and in whole body calcium balance in knockout mice of either sex on normal or high-calcium diet, with the exception that males were in slightly positive calcium balance on normal-calcium diet. Our results show that claudin-2 contributes to intestinal permeability to calcium but does not play a significant role in net intestinal calcium absorption or secretion.<b>NEW & NOTEWORTHY</b> Global claudin-2 knockout mice have hypercalciuria due to both intestinal overabsorption of calcium and a renal calcium leak. Here, we generated intestine-specific claudin-2 knockout mice. Ileal and colonic calcium permeability were reduced, but surprisingly these animals exhibited only transient hypercalciuria for 1 wk after weaning. Thus, claudin-2 contributes to intestinal permeability to calcium but does not play a significant role in intestinal calcium absorption or secretion.