Abstract
Up to 15% of the population have mild to moderate chronic hypomagnesemia, which is associated with type 2 diabetes mellitus, hypertension, metabolic syndrome, and chronic kidney disease. The kidney is the key organ for magnesium homeostasis, but our understanding of renal magnesium regulation is very limited. Uromodulin (UMOD) is the most abundant urinary protein in humans, and here we report that UMOD has a role in renal magnesium homeostasis. Umod-knockout (Umod-/-) mice excreted more urinary magnesium than WT mice and displayed up-regulation of genes promoting magnesium absorption. The majority of magnesium is absorbed in the thick ascending limb. However, both mouse strains responded similarly to the diuretic agent furosemide, indicating appropriate function of the thick ascending limb in the Umod-/- mice. Magnesium absorption is fine-tuned in the distal convoluted tubule (DCT) via the apical magnesium channel transient receptor potential melastatin 6 (TRPM6). We observed decreased apical Trpm6 staining in the DCT of Umod-/- mice. Applying biotinylation assays and whole-cell patch-clamp recordings, we found that UMOD enhances TRPM6 cell-surface abundance and current density from the extracellular space. UMOD physically interacted with TRPM6 and thereby impaired dynamin-dependent TRPM6 endocytosis. WT mice fed a low-magnesium diet had an increased urinary UMOD secretion compared with the same mice on a regular diet. Our results suggest that increased urinary UMOD secretion in low-magnesium states reduces TRPM6 endocytosis and thereby up-regulates TRPM6 cell-surface abundance to defend against further urinary magnesium losses.
Highlights
Up to 15% of the population have mild to moderate chronic hypomagnesemia, which is associated with type 2 diabetes mellitus, hypertension, metabolic syndrome, and chronic kidney disease
Uromodulin (UMOD) is the most abundant urinary protein in humans, and here we report that UMOD has a role in renal magnesium homeostasis
Our results suggest that increased urinary UMOD secretion in low-magnesium states reduces transient receptor potential melastatin 6 (TRPM6) endocytosis and thereby up-regulates TRPM6 cell-surface abundance to defend against further urinary magnesium losses
Summary
Umod؊/؊ mice display urinary Mg2؉ wasting and decreased apical Trpm abundance in the DCT. To study whether UMOD has an effect on TRPM6 channel current density, we co-transfected HEK293 cells with TRPM6 and control or UMOD. Co-expression of TRPM6 and UMOD increased TRPM6 current density significantly by a factor of 4.6 compared with control (Fig. 2, C and D). Our studies showed that animals fed a low-Mg2ϩ diet had a significantly elevated, 2-fold stronger, urinary UMOD protein band compared with urine obtained on a regular diet (Fig. 7, A and B). These data are consistent with the systemic Mg2ϩ state influencing the urinary UMOD secretion and point toward a feedback mechanism targeting systemic Mg2ϩ homeostasis
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
