Epithelial magnesium transport by TRPM6 is essential for prenatal development and adult survival

Chubanov, Vladimir; Ferioli, Silvia; Wisnowsky, Annika; Simmons, David G.; Leitzinger, Christin; Einer, Claudia; Jonas, Wenke; Shymkiv, Yuriy; Bartsch, Harald; Braun, Attila; Akdogan, Banu; Mittermeier, Lorenz; Sytik, Ludmila; Friedrich, Torben; Jurinović, Vindi; Vorst, Emiel P. C. van der; Yildirim, Önder; Sotlar, Karl; Schürmann, A; Zierler, Susanna; Zischka, Hans; Ryazanov, Alexey G.; Gudermann, Thomas

doi:10.7554/elife.20914

Cited by 105 publications

(129 citation statements)

References 84 publications

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“…We hypothesized that DBA/2 mice are more prone to calcification than are C57BL/6 mice, because of renal Mg wasting [37] and thus loss of systemic Mg, a potent crystal nucleation inhibitor [38]. A recent study showed however, that kidney-specific TRPM6 knockout mice had no phenotype in contrast to intestine-specific knockout [39]. These results recapitulated clinical studies with patients with TRPM6 null mutations clearly showing that a defect in intestinal Mg2+ uptake causes hypomagnesemia.…”

Section: Discussionmentioning

confidence: 70%

Microvasculopathy And Soft Tissue Calcification In Mice Are Governed by Fetuin-A, Pyrophosphate And Magnesium

Babler

Schmitz

Büscher

et al. 2019

Preprint

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Objective -Calcifications can disrupt organ function in the cardiovascular system and the kidney, and are particularly common in patients with chronic kidney disease (CKD). Fetuin-A deficient mice maintained against the genetic background DBA/2 exhibit particularly severe soft tissue calcifications, while fetuin-A deficient C57BL/6 mice remain healthy. We employed molecular genetic analysis to identify risk factors of calcification in fetuin-A deficient mice. We sought to identify pharmaceutical therapeutic target that could be influenced by dietary of parenteral supplementation.Approach and Results -We studied the progeny of an intercross of fetuin-A deficient DBA/2 and C57BL/6 mice to identify candidate risk genes involved in calcification. We determined that a hypomorphic mutation of the Abcc6 gene, a liver ATP transporter supplying systemic pyrophosphate, and failure to regulate the TRPM6 magnesium transporter in kidney were associated with severity of calcification. Calcification prone fetuin-A deficient mice were alternatively treated with dietary phosphate restriction, magnesium supplementation, or by parenteral administration of fetuin-A or pyrophosphate. All treatments markedly reduced soft tissue calcification, demonstrated by computed tomography, histology and tissue calcium measurement.Conclusions -We show that pathological ectopic calcification in fetuin-A deficient DBA/2 mice is caused by a compound deficiency of three major extracellular and systemic inhibitors of calcification, namely fetuin-A, pyrophosphate, and magnesium. All three of these are individually known to contribute to stabilize protein-mineral complexes and thus inhibit mineral precipitation from extracellular fluid. We show for the first time a compound triple deficiency that can be treated by simple dietary or parenteral supplementation. This is of special importance in patients with advanced CKD, who commonly exhibit reduced serum fetuin-A, pyrophosphate and magnesium levels.

show abstract

Section: Discussionmentioning

confidence: 70%

Microvasculopathy And Soft Tissue Calcification In Mice Are Governed by Fetuin-A, Pyrophosphate And Magnesium

Babler

Schmitz

Büscher

et al. 2019

Preprint

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“…Interestingly, PLC requires Mg 2+ to function (36,37). Moreover, hypomagnesemic Trpm6 knockout mice have elevated serum and liver sphingolipid levels (23). How hypomagnesemia affects phospholipid and sphingolipid metabolism requires further investigation.…”

Section: Discussionmentioning

confidence: 99%

“…When blood Mg 2+ levels decrease, the colon compensates by increasing the uptake of Mg 2+ from the diet (23). Indeed, in mice fed a low dietary Mg 2+ content, colonic Trpm6 mRNA expression was up-regulated ( Fig.…”

Section: An Hfd Reduces Mrna Expression Of Trpm6 In Distal Colonmentioning

confidence: 96%

Renal phospholipidosis and impaired magnesium handling in high‐fat‐diet–fed mice

et al. 2019

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Hypomagnesemia (blood Mg2+ concentration <0.7 mM) is a common electrolyte disorder in patients with type 2 diabetes (T2D), but the etiology remains largely unknown. In patients with T2D, reduced blood Mg2+ levels are associated with an increased decline in renal function, independent of glycemic control and hypertension. To study the underlying mechanism of this phenomenon, we investigated the renal effects of hypomagnesemia in high‐fat‐diet (HFD)‐fed mice. In mice fed a low dietary Mg2+, the HFD resulted in severe hypomagnesemia within 4 wk. Renal or intestinal Mg2+ wasting was not observed after 16 wk on the diets. Despite the absence of urinary or fecal Mg2+ loss, the HFD induced a reduction in the mRNA expression transient receptor potential melastatin type 6 in both the kidney and colon. mRNA expression of distal convoluted tubule (DCT)‐specific genes was down‐regulated by the LowMg‐HFD, indicating atrophy of the DCT. The low dietary Mg2+ resulted in severe HFD‐induced proximal tubule phospholipidosis, which was absent in mice on a NormalMg‐HFD. This was accompanied by albuminuria, moderate renal damage, and alterations in renal energy metabolism, including enhanced gluconeo‐genesis and cholesterol synthesis. In conclusion, this study shows that hypomagnesemia is a consequence of diet‐induced obesity and insulin resistance. Moreover, hypomagnesemia induces major structural changes in the diabetic kidney, including proximal tubular phospholipidosis, providing a novel mechanism for the increased renal decline in patients with hypomagnesemic T2D.—Kurstjens, S., Smeets, B., Overmars‐Bos, C., Dijkman, H. B., den Braanker, D. J. W., de Bel, T., Bindels, R. J. M., Tack, C. J. J., Hoenderop, J. G. J., de Baaij, J. H. F. Renal phospholipidosis and impaired magnesium handling in high‐fat‐diet–fed mice. FASEB J. 33, 7192–7201 (2019). http://www.fasebj.org

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“…Importantly, global TRPM6 disruption in mice is embryonic lethal (6,7). Mice with loss of TRPM6 at intermediate developmental time points manifest a reduced life span and skeletal deformations, in addition to mild hypomagnesemia (5). These data indicate that, much like TRPM7 (8), TRPM6 may be critical for normal, developmental, tissue-specific regulation of gene activity.…”

Section: For a Recent Review)mentioning

confidence: 98%

“…The mechanisms by which mutations in TRPM6 lead to HSH are unknown, although several studies stress the importance of TRPM6-mediated Mg 2+ conductance (3)(4)(5). Importantly, global TRPM6 disruption in mice is embryonic lethal (6,7).…”

Section: For a Recent Review)mentioning

confidence: 99%

Histone phosphorylation by TRPM6’s cleaved kinase attenuates adjacent arginine methylation to regulate gene expression

Krapivinsky

Renthal

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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TRPM6 and TRPM7 are members of the melastatin-related transient receptor potential (TRPM) subfamily of ion channels. Deletion of either gene in mice is embryonically lethal. TRPM6/7 are the only known examples of single polypeptides containing both an ion channel pore and a serine/threonine kinase (chanzyme). Here we show that the C-terminal kinase domain of TRPM6 is cleaved from the channel domain in a cell type-specific fashion and is active. Cleavage requires that the channel conductance is functional. The cleaved kinase translocates to the nucleus, where it is strictly localized and phosphorylates specific histone serine and threonine (S/T) residues. TRPM6-cleaved kinases (M6CKs) bind subunits of the protein arginine methyltransferase 5 (PRMT5) molecular complex that make important epigenetic modifications by methylating histone arginine residues. Histone phosphorylation by M6CK results in a dramatic decrease in methylation of arginines adjacent to M6CK-phosphorylated amino acids. Knockout of TRPM6 or inactivation of its kinase results in global changes in histone S/T phosphorylation and changes the transcription of hundreds of genes. We hypothesize that M6CK associates with the PRMT5 molecular complex in the nucleus, directing M6CK to a specific genomic location and providing site-specific histone phosphorylation. M6CK histone phosphorylation, in turn, regulates transcription by attenuating the effect of local arginine methylation.A mong the several hundred genes encoding cation channels, the melastatin-related transient receptor potential family members TRPM6 and TRPM7 are unique in also being serine/ threonine (S/T) kinases (1). The TRPM6 channel kinase was brought to greater attention when mutations in this chanzyme were found to be the cause of familial hypomagnesemia with secondary hypocalcemia (HSH; see ref. 2 for a recent review). Characterized by severe hypomagnesemia, infants with HSH suffer tetany and refractory seizures shortly after birth, resulting in permanent neurological damage or death if untreated. The mechanisms by which mutations in TRPM6 lead to HSH are unknown, although several studies stress the importance of TRPM6-mediated Mg 2+ conductance (3-5). Importantly, global TRPM6 disruption in mice is embryonic lethal (6, 7). Mice with loss of TRPM6 at intermediate developmental time points manifest a reduced life span and skeletal deformations, in addition to mild hypomagnesemia (5). These data indicate that, much like TRPM7 (8), TRPM6 may be critical for normal, developmental, tissue-specific regulation of gene activity.Recently, our laboratory uncovered a signaling pathway mediated by TRPM7, a channel sharing 52% homology with TRPM6, whereby the functional S/T kinase at the carboxyl terminus of TRPM7 is proteolytically cleaved from the channel domain, forming cleaved kinase fragments (M7CKs) that translocate to the nucleus (9). There, M7CKs bind components of chromatin-remodeling complexes to ultimately phosphorylate specific S/T residues of histones, regulate selected histone acetylatio...

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Epithelial magnesium transport by TRPM6 is essential for prenatal development and adult survival

Cited by 105 publications

References 84 publications

Microvasculopathy And Soft Tissue Calcification In Mice Are Governed by Fetuin-A, Pyrophosphate And Magnesium

Microvasculopathy And Soft Tissue Calcification In Mice Are Governed by Fetuin-A, Pyrophosphate And Magnesium

Renal phospholipidosis and impaired magnesium handling in high‐fat‐diet–fed mice

Histone phosphorylation by TRPM6’s cleaved kinase attenuates adjacent arginine methylation to regulate gene expression

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