The TRPM7 channel kinase regulates store‐operated calcium entry

Faouzi, Malika; Kilch, Tatiana; Horgen, F. David; Fleig, Andrea; Penner, Reinhold

doi:10.1113/jp274006

Cited by 94 publications

(114 citation statements)

References 77 publications

Supporting

Mentioning

105

Contrasting

Order By: Relevance

“…Indeed, using the TRPM7 inhibitor NS8593 suppressed TRPM7 expression and cell proliferation both in tubular epithelial cells and interstitial cells, prevented upregulation of Smad2/ Smad3 signaling, and attenuated renal atrophy and fibrosis. These effects, combined with the known inhibitory effects of the compound on both ion channel and kinase function of TRPM7 22,23 as well as the inhibition of pro-proliferative signaling of macrophages 13,14 , indicate that TRPM7 may represent a promising therapeutic target in kidney fibrosis and TRPM7 inhibitors may act as anti-fibrotic pharmacological tools in this process.…”

Section: Discussionmentioning

confidence: 99%

“…SOCE is critically involved in cytokine production through calcium-release activated Ca 2+ (CRAC) channels via STIM1, STIM2 and Orai1 3,23,32,33 . Furthermore, SOCE activity is facilitated by TRPM7 via its kinase function 23,34 . The strongly enhanced expression level of TRPM7 in UUO kidneys might therefore not only lead to enhanced tubular epithelial cell proliferation, but also to enhanced SOCE, and with this, enhanced cytokine-production and aggravation of fibrosis.…”

Section: Discussionmentioning

confidence: 99%

“…The strongly enhanced expression level of TRPM7 in UUO kidneys might therefore not only lead to enhanced tubular epithelial cell proliferation, but also to enhanced SOCE, and with this, enhanced cytokine-production and aggravation of fibrosis. NS8593 is known to act both on TRPM7 channel function as well as TRPM7 kinase activity 22,23 . While NS8593 does not interfere with SOCE directly, the drug suppresses SOCE through inhibition of the TRPM7 kinase domain 23 .…”

Section: Discussionmentioning

confidence: 99%

“…We next asked the question whether pharmacological suppression of TRPM7 channel activity would have protective effects in the UUO animal model. To this end, we first assessed the ability of NS8593 -a small conductance potassium channel inhibitor that very efficiently suppresses TRPM7 currents as well 13,22,23 -to suppress intracellular fluorescence quenching of Fura-2 by manganese (Mn 2+ ) ions permeating through TRPM7 24,25 in epithelial kidney NRK-52E and fibroblast NRK-49F model cells. We performed a dose-response analysis for NS8593 on intracellular Fura-2 quench induced by Mn 2+ binding in both cell lines using a fluorescent 96-well kinetic plate reader 24,25 (Fig.…”

Section: Ns8593 Suppresses Manganese Influx In Epithelial and Fibroblmentioning

confidence: 99%

“…Unfortunately, there are no treatment modalities that are effective in halting the progression of most chronic kidney diseases associated with kidney fibrosis 21 . NS8593 is a small conductance potassium channel inhibitor that also significantly affects TRPM7 22,23 and has been shown to inhibit the proliferation and polarization of human macrophages mediated by TRPM7 13 . It therefore represents a useful pharmacological tool to investigate the role of TRPM7 in the pathophysiology of kidney fibrosis and evaluating this channel as a potential therapeutic target.…”

mentioning

confidence: 99%

See 4 more Smart Citations

TRPM7 contributes to progressive nephropathy

Suzuki

Penner

Fleig

2020

Sci Rep

Self Cite

View full text Add to dashboard Cite

TRPM7 belongs to the Transient Receptor Potential Melastatin family of ion channels and is a divalent cation-conducting ion channel fused with a functional kinase. TRPM7 plays a key role in a variety of diseases, including neuronal death in ischemia, cancer, cardiac atrial fibrillation, malaria invasion. TRPM7 is aberrantly over-expressed in lung, liver and heart fibrosis. It is also overexpressed after renal ischemia-reperfusion, an event that induces kidney injury and fibrosis. However, the role of TRPM7 in kidney fibrosis is unclear. Using the unilateral ureteral obstruction (UUO) mouse model, we examined whether TRPM7 contributes to progressive renal damage and fibrosis. We find that TRPM7 expression increases in UUO kidneys. Systemic application of NS8593, a known TRPM7 inhibitor, prevents kidney atrophy in UUO kidneys, retains tubular formation, and reduces TRPM7 expression to normal levels. Cell proliferation of both tubular epithelial cells and interstitial cells is reduced by NS8593 treatment in UUO kidneys, as are TGF-β1/Smad signaling events. We conclude that TRPM7 is upregulated during inflammatory renal damage and propose that pharmacological intervention targeting TRPM7 may prove protective in progressive kidney fibrosis.TRPM7 belongs to the Transient Receptor Potential (TRP) Melastatin family of ion channels, but is unique in that its ion channel domain is fused with a functional serine/threonine kinase 1 . TRPM7 was the first ion channel shown to conduct a range of divalent cations 2,3 , including physiologically essential divalent cations such as Ca 2+ , Mg 2+ , Zn 2+ , Ni 2+ , Mn 2+ , and Co 2+ . Ample evidence supports TRPM7 to be critical in regulating Mg 2+ homeostasis 1 and play a key role in a variety of diseases, including neuronal death in ischemia 4 , renal ischemia 5 , and cardiac atrial fibrillation 6 . TRPM7 is expressed ubiquitously in mammals, and is key in driving cell growth and proliferation, linking the protein to hyperproliferative diseases such cancer 1,7,8 and pulmonary, hepatic, and cardiac fibrosis 6,9-12 . Tissue fibrosis refers to a number of conditions that cause interstitial organ damage followed by inflammation and maladaptive wound healing eventually leading to fibrosis and chronic disease in the organ affected. TRPM7 overexpression leads to fibrosis through the TGF-β signaling pathway 9-11 . Recent in vitro data show that TRPM7 plays a pivotal role in progressive inflammatory and fibrotic disease by promoting excessive extracellular matrix (ECM) deposition 9 . It regulates proliferation and differentiation of fibroblasts 11 and proliferation and polarization of macrophages 13 as well as their Ca 2+ -dependent activation 14 . A recent study supports this hypothesis, as genetic suppression of TRPM7 in a kidney transplantation mouse model alleviated progressive inflammatory kidney fibrosis 15 .In the kidney, cell proliferation is a central response to injury that culminates in the development of fibrosis and renal failure. Unilateral ureteral obstruction (UUO) is a wide...

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Ns8593 Suppresses Manganese Influx In Epithelial and Fibroblmentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

TRPM7 contributes to progressive nephropathy

Suzuki

Penner

Fleig

2020

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

TRPM6 and TRPM7: Novel players in cell intercalation during vertebrate embryonic development

Runnels

Komiya

2020

Developmental Dynamics

View full text Add to dashboard Cite

A common theme in organogenesis is how the final structure of organs emerge from epithelial tube structures, with the formation of the neural tube being one of the best examples. Two types of cell movements co‐occur during neural tube closure involving the migration of cells toward the midline of the embryo (mediolateral intercalation or convergent extension) as well as the deep movement of cells from inside the embryo to the outside of the lateral side of the neural plate (radial intercalation). Failure of either type of cell movement will prevent neural tube closure, which can produce a range of neural tube defects (NTDs), a common congenital disease in humans. Numerous studies have identified signaling pathways that regulate mediolateral intercalation during neural tube closure. Less understood are the pathways that govern radial intercalation. Using the Xenopus laevis system, our group reported the identification of transient receptor potential (TRP) channels, TRPM6 and TRPM7, and the Mg2+ ion they conduct, as novel and key factors regulating both mediolateral and radial intercalation during neural tube closure. Here we broadly discuss tubulogenesis and cell intercalation from the perspective of neural tube closure and the respective roles of TRPM7 and TRPM6 in this critical embryonic process.

show abstract

Cytocompatibility, cell‐material interaction, and osteogenic differentiation of MC3T3‐E1 pre‐osteoblasts in contact with engineered Mg/PLA composites

Ali,

Ordoño,

Kopp

et al. 2024

J Biomedical Materials Res

View full text Add to dashboard Cite

Bioabsorbable Mg wire‐reinforced poly‐lactic acid (PLA) matrix composites are potential candidate for load‐bearing orthopedic implants offering tailorable mechanical and degradation properties by stacking sequence, volume fraction and surface modification of Mg wires. In this study, we investigated the cytocompatibility, cell‐material interaction, and bone differentiation behavior of MC3T3‐E1 pre‐osteoblast cells for medical‐grade PLA, Mg/PLA, and PEO‐Mg/PLA (having PEO surface modification on Mg wires) composites. MTT and live/dead assay showed excellent biocompatibility of both composites while cell‐material interaction analysis revealed that cells were able to adhere and proliferate on the surface of composites. Cells on the longitudinal surface of composites showed a high and uniform cell density while those on transversal surfaces initially avoided Mg regions but later migrated back after the formation of the passivation layer. Bone differentiation tests showed that cells in extracts of PLA and composites were able to initiate the differentiation process as osteogenesis‐related gene expressions, alkaline phosphatase protein quantity, and calcium mineralization increased after 7 and 14 days of culture. Interestingly, the bone differentiation response of PEO‐Mg/PLA composite was found to be similar to medical‐grade PLA, proving its superiority over Mg/PLA composite.

show abstract

The TRPM7 channel kinase regulates store‐operated calcium entry

Cited by 94 publications

References 77 publications

TRPM7 contributes to progressive nephropathy

TRPM7 contributes to progressive nephropathy

TRPM6 and TRPM7: Novel players in cell intercalation during vertebrate embryonic development

Cytocompatibility, cell‐material interaction, and osteogenic differentiation of MC3T3‐E1 pre‐osteoblasts in contact with engineered Mg/PLA composites

Contact Info

Product

Resources

About