Kidney Week

Abstract: FR-PO308

The Influence of MUC1 on Mg2+ Handling

Session Information

• Bone and Mineral Metabolism: Basic
  November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Bone and Mineral Metabolism

• 501 Bone and Mineral Metabolism: Basic

Authors

• Lam, Tracey, University of Pittsburgh, Pittsburgh, Pennsylvania, United States

Tracey Lam,

• Al-bataineh, Mohammad M., University of Pittsburgh, Pittsburgh, Pennsylvania, United States

Mohammad M. Al-bataineh,

• Marciszyn, Allison L., University of Pittsburgh, Pittsburgh, Pennsylvania, United States

Allison L. Marciszyn,

• Ye, Lorena, University of Pittsburgh, Pittsburgh, Pennsylvania, United States

Lorena Ye,

• Singh, Amrit, University of Pittsburgh, Pittsburgh, Pennsylvania, United States

Amrit Singh,

• Poland, Paul A., University of Pittsburgh, Pittsburgh, Pennsylvania, United States

Paul A. Poland,

• Kinlough, Carol L., University of Pittsburgh, Pittsburgh, Pennsylvania, United States

Carol L. Kinlough,

• Emlet, David R., University of Pittsburgh, Pittsburgh, Pennsylvania, United States

David R. Emlet,

• Ray, Evan C., University of Pittsburgh, Pittsburgh, Pennsylvania, United States

Evan C. Ray,

• Hughey, Rebecca P., University of Pittsburgh, Pittsburgh, Pennsylvania, United States

Rebecca P. Hughey,

Background

Numerous genomic studies find an association between the common MUC1 polymorphism rs4072037 (minor allele frequency 21-47%) and circulating Mg²⁺ levels. This polymorphism in exon 1 of MUC1 alters mRNA splicing, elongating the N-terminus of mature MUC1. It is referred to as the long-signal peptide variant (LSP), as compared to the short-signal peptide variant (SSP). Although human genome association studies have found an association between the LSP variant and hypomagnesemia, no studies have demonstrated an effect of MUC1 on Mg²⁺ balance.

MUC1 is known to enhance cell surface localization of Ca²⁺-selective TRP channels (TRPV5 and TRPV6). MUC1 is co-expressed with the Mg²⁺-selective channel, TRPM6 in the kidney’s distal convoluted tubule (DCT). TRPM6 is a key mediator of renal Mg²⁺ handling. Reduced TRPM6 cell surface expression in response to blockage of the epidermal growth factor receptor (EGFR), leads to urinary Mg²⁺ wasting and hypomagnesemia.

We hypothesized that MUC1 influences TRPM6 cell surface expression, contributing to renal tubular reabsorption of Mg²⁺, and that LSP-MUC1 does this less effectively than SSP-MUC1.

Methods

We examined plasma Mg²⁺ levels in Muc1^-/- mice and studied MUC1 and TRPM6 expression in polarized MDCK cells and in human kidney tissue samples.

Results

We find that Muc1^-/- mice are hypomagnesemic. In polarized MDCK cells in culture, MUC1 co-immunoprecipitates with TRPM6 and its binding partner, TRPM7. MUC1 enhances cell surface expression of TRPM6 and TRPM7. Although the majority of MUC1 is expressed at the apical surface of polarized epithelial cells, a small fraction is expressed basolaterally, where EGFR is located. Both in MDCK cells and in human kidney tissue, that fraction of MUC1 is reduced in the LSP variant as compared to the SSP variant. EGFR is more heavily phosphorylated in response to basolateral EGF in MDCK cells expressing SSP-MUC1 compared with LSP-MUC1, suggesting that SSP-MUC1 enhances activation of the EGFR receptor, promoting activation of TRPM6.

Conclusion

These studies provide a mechanistic explanation for the influence of MUC1 upon Mg²⁺ homeostasis. On-going studies are exploring the specific importance of kidney tubule MUC1 for TRPM6 activity and Mg²⁺ balance and EGFR-dependence of differences in TRPM6 cell surface expression associated with the LSP vs SSP MUC1 variants.

Funding

• NIDDK Support