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Uromodulin regulates renal magnesium homeostasis through the ion channel transient receptor potential melastatin 6 (TRPM6).

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.

SUBMITTER: Nie M

PROVIDER: S-EPMC6200953 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Flavaglines Stimulate Transient Receptor Potential Melastatin Type 6 (TRPM6) Channel Activity.

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Project description:BACKGROUND AND PURPOSE:9-Phenanthrol, known as a specific inhibitor of the transient receptor potential melastatin 4 (TRMP4) channel, has been shown to modulate cardiac electrical activity and exert antiarrhythmic effects. However, its pharmacological effects remain to be fully explored. Here, we tested the hypothesis that cardiac sodium current inhibition contributes to the cardioprotective effect of 9-phenanthrol. EXPERIMENTAL APPROACH:Single ventricular myocytes (VMs) and Purkinje cells (PCs) were enzymatically isolated from rabbits. Arterially perfused rabbit wedge preparations were also used, and transmural electrocardiogram and endocardial action potentials (APs) were simultaneously recorded. Wild-type and mutated human recombinant SCN5A were expressed in HEK293 cells. Anemonia toxin II (ATX-II) was used to amplify the late sodium current (INaL ) and induce arrhythmias. Whole-cell patch clamp technique was used to record APs and ionic currents. KEY RESULTS:9-Phenanthrol (10-50 ?M) stabilized ventricular repolarization and abolished arrhythmias induced by ATX-II in both isolated VMs, PCs and wedge preparations. Further study revealed that 9-phenanthrol modulated the gating properties of cardiac sodium channels and dose-dependently inhibited INaL and peak sodium current (INaP ) in VMs with an IC50 of 18 and 71.5 ?M respectively. Its ability to inhibit INaL was further confirmed in PCs and HEK293 cells expressing SCN5A mutations. CONCLUSIONS AND IMPLICATIONS:Our results indicate that 9-phenanthrol modulates the gating properties of cardiac sodium channels and inhibits INaL and INaP , which may contribute to its antiarrhythmic and cardioprotective effects.

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