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

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 t...
Source: Journal of Biological Chemistry - Category: Chemistry Authors: Tags: Molecular Bases of Disease Source Type: research

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Conclusion Activation of the Nrf2-dependent antioxidant system plays an important role in cell defense against oxidative stress damage, whereas the insufficiency of the Nrf2 system is associated with multiple aspects of the genesis and progression of metabolic diseases, posing a great risk to the cardiovascular system (Figure 1). The systemic increase of Nrf2 activity by several activators may be beneficial in the treatment of metabolic diseases. In addition, selective upregulation of Nrf2 genes may represent a potential therapy in obesity, diabetes and atherosclerosis. Looking to the future, experimental research that el...
Source: Frontiers in Pharmacology - Category: Drugs & Pharmacology Source Type: research
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Source: International Journal of Cardiology - Category: Cardiology Authors: Tags: Editorial Source Type: research
Abstract Type 2 diabetes mellitus (T2DM) substantially increases the risk of cardiovascular events, including heart failure (HF), due to complications such as hypertension, obesity and dyslipidemia based on metabolic syndrome, which plays the central pathological role in HF. A reason is that T2DM causes left ventricular (LV) diastolic dysfunction beginning in the early phase of the disease, which in turn increases the risk of development of HF independently of the control of blood glucose levels, blood pressure or the presence of coronary artery diseases. Intracellular metabolic disorders and increased oxidative s...
Source: Clin Med Res - Category: Research Authors: Tags: J Clin Med Res Source Type: research
Publication date: Available online 5 June 2018Source: Seminars in Cell &Developmental BiologyAuthor(s): Robert L. ChevalierAbstractThere is a global epidemic of chronic kidney disease (CKD) characterized by a progressive loss of nephrons, ascribed in large part to a rising incidence of hypertension, metabolic syndrome, and type 2 diabetes mellitus. There is a ten-fold variation in nephron number at birth in the general population, and a 50% overall decrease in nephron number in the last decades of life. The vicious cycle of nephron loss stimulating hypertrophy by remaining nephrons and resulting in glomerulosclerosis h...
Source: Seminars in Cell and Developmental Biology - Category: Cytology Source Type: research
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Source: Endocrine - Category: Endocrinology Source Type: research
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Source: Clinics in Dermatology - Category: Dermatology Authors: Source Type: research
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Source: Diabetes and Metabolism Journal - Category: Endocrinology Tags: Diabetes Metab J Source Type: research
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Source: Diabetes and Metabolic Syndrome: Clinical Research and Reviews - Category: Endocrinology Source Type: research
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Source: Current Medicinal Chemistry - Category: Chemistry Authors: Tags: Curr Med Chem Source Type: research
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Source: Pulse - Category: Cardiology Source Type: research
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