Disruption of Claudin‐2 and Trpv6 Results in Hypocalcemia, Hypercalciuria, and Altered Bone Microarchitecture in Mice

Transepithelial calcium absorption occurs via a transcellular or paracellular pathway. The intestinal transcellular pathway relies, at least partially, on the apical calcium channel transient receptor potential vanilloid 6 (TRPV6), whereas paracellular calcium (re)absorption occurs through tight junction proteins, including claudin‐2 (CLDN2). Both CLDN2 and TRPV6 are also expressed in the kidney. CLDN2 contributes to proximal tubular calcium reabsorption, whereas the functional relevance of TRPV6 remains unclear. Cldn2 −/− knockout mice exhibit reduced intestinal calcium permeability and hypercalciuria, while maintaining normal bone mineral density (BMD), plasma calcium, and calciotropic hormone levels. Trpv6 D541A/D541A pore mutants were reported to have normal urinary and plasma calcium levels, despite reduced intestinal calcium absorption on a low calcium diet. However, we found subtle sex‐specific differences in calcium homeostasis in these mice. We hypothesized that transcellular and paracellular calcium absorption pathways compensate for one another in these models. To test this, we crossed Cldn2 −/− with Trpv6 D541A/D541A mice to generate a functional double knockout (DKO, Cldn2 −/− / Trpv6 D541A/D541A ). These mice displayed hypocalcemia, elevated calcitriol, and reduced BMD. Surprisingly, despite unchanged fecal calcium excretion, renal calcium wasting was greater than in Cldn2 −/− mice. Gene expression studies revealed increased calbindin‐D 9k expression in the proximal colon and calbindin‐D 28k in the kidney, consistent with partial compensation by the colon and distal nephron. Together, these findings indicate that combined impairment of paracellular and transcellular calcium transport reduces intestinal and renal calcium (re)absorption, leading to hypocalcemia and increased calcitriol levels, and highlight a role for TRPV6 in distal nephron calcium handling.