Mucin 1 is Necessary for TrpV5 Localization in the Kidney's Distal Convoluted Tubule and Normal Bone Architecture

Abstract

Mucin 1 (Muc1 in mice and MUC1 in humans) is a heavily glycosylated transmembrane protein expressed in numerous epithelia. Muc1 interacts with other glycoproteins via interaction with galectins, which bind β‐galactoside sugars. Genome‐wide association data suggest a link between MUC1 polymorphism and bone density. MUC1 exogenously expressed in cultured cells physically interacts with calcium‐selective ion channel TRPV5, increasing cell surface expression and activity in a galectin 3‐dependent fashion. TrpV5 knock‐out (KO) mice exhibit impaired reabsorption of filtered Ca2+ in the kidney's distal convoluted tubule (DCT), resulting in hypercalciuria and diminished trabecular and cortical bone thickness. We hypothesize that interaction between Muc1 and TrpV5 is necessary for normal Ca2+ homeostasis and bone architecture. We examined density and architecture in Muc1 KO mice using μCT of lumbar vertebrae. Male Muc1 KO mice exhibit reduced lumbar vertebral cortical and trabecular thickness, with increased surface area/volume. Muc1 KO mice exhibit similar whole‐blood ionized Ca2+ levels, but increased kidney 1‐α‐hydroxylase levels, suggestive of bodily Ca2+ depletion. We observe that TrpV5 is mis‐localized in the DCT of Muc1 KO mice, suggesting that impaired renal tubular Ca2+ reabsorption may contribute to this Ca2+ depletion. Additionally, TrpV5 is mis‐localized in the DCT in galectin‐3 KO mice, consistent with a role for galectin 3 in mediating Muc1‐TrpV5 interaction. Taken together, these findings suggest that Muc1 plays a role in bodily Ca2+ homeostasis and bone physiology by enhancing cell surface expression of TrpV5.Support or Funding InformationNIDDK K08 DK110332, K01 DK109038, P30 DK079307This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.