Bone loss and renal Ca 2+ wasting in experimental colitis is accompanied by downregulation of TRPV5 in renal distal convoluted tubules

Dysregulated Ca 2+ homeostasis likely contributes to the etiology of IBD‐associated bone loss. Experimental colitis leads to decreased expression of Klotho, a protein which supports renal Ca 2+ reabsorption by stabilizing TRPV5 channel on the apical membrane of distal tubule epithelial cells. We investigated whether colitis leads to changes in renal Ca 2+ handling and expression of TRPV5 utilizing TNBS, and two adoptive T‐cell transfer models (CD4 + CD45RB Hi or CD4 + IL10 −/− ). Colitic mice had normal serum levels of Ca 2+ and PTH. μCT analysis demonstrated changes in bone structure along with changes in serum sRANKL, IL‐6, osteocalcin, TNF, and total serum tDPD crosslinks. Increased fractional Ca 2+ excretion was accompanied by reduction of TRPV5 protein expression, with concomitant increase in its sialylation status. In mIMCD3 cells transduced with Ad‐TRPV5, proinflammatory cytokines reduced TRPV5 surface expression followed by its degradation. TNF induced interaction of TRPV5 with UBR4 ubiquitin ligase and siRNA‐mediated UBR4 knockdown prevented TNF induced TRPV5 degradation. The cytokine effect on TRPV5 was not observed in cells stably transfected with membrane‐bound Klotho. We propose that TNF and IFNγ act to decrease Klotho expression and activity, increased sialylation of TRPV5, impaired interaction of TRPV5 and galectin‐1, and ultimately to UBR4‐dependent endocytosis and degradation of TRPV5.