Transcriptional Control of Trpm6 by the Nuclear Receptor FXR

Kim, Eun Young; Lee, Jae Man

doi:10.3390/ijms23041980

Cited by 7 publications

(4 citation statements)

References 77 publications

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“…Indeed, apical plasma membrane expression of AQP2 is reduced in collecting duct cells expressing an Hnf1b mutant [ 2 ]. Interestingly, FXR directly activates the expression of Mg 2+ channel Trpm6 in mouse intestines [ 40 ]. Hence, HNF1β might indirectly regulate Trpm6 expression in the intestines and kidneys through FXR, contributing to disturbed Mg 2+ homeostasis in HNF1β patients.…”

Section: Mechanisms Of Disturbed Electrolyte Transport In Adtkd-hnf1β...mentioning

confidence: 99%

Mechanisms of ion transport regulation by HNF1β in the kidney: beyond transcriptional regulation of channels and transporters

Tholen

Hoenderop

Baaij

2022

Pflugers Arch - Eur J Physiol

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Hepatocyte nuclear factor 1β (HNF1β) is a transcription factor essential for the development and function of the kidney. Mutations in and deletions of HNF1β cause autosomal dominant tubule interstitial kidney disease (ADTKD) subtype HNF1β, which is characterized by renal cysts, diabetes, genital tract malformations, and neurodevelopmental disorders. Electrolyte disturbances including hypomagnesemia, hyperuricemia, and hypocalciuria are common in patients with ADTKD-HNF1β. Traditionally, these electrolyte disturbances have been attributed to HNF1β-mediated transcriptional regulation of gene networks involved in ion transport in the distal part of the nephron including FXYD2, CASR, KCNJ16, and FXR. In this review, we propose additional mechanisms that may contribute to the electrolyte disturbances observed in ADTKD-HNF1β patients. Firstly, kidney development is severely affected in Hnf1b-deficient mice. HNF1β is required for nephron segmentation, and the absence of the transcription factor results in rudimentary nephrons lacking mature proximal tubule, loop of Henle, and distal convoluted tubule cluster. In addition, HNF1β is proposed to be important for apical-basolateral polarity and tight junction integrity in the kidney. Interestingly, cilia formation is unaffected by Hnf1b defects in several models, despite the HNF1β-mediated transcriptional regulation of many ciliary genes. To what extent impaired nephron segmentation, apical-basolateral polarity, and cilia function contribute to electrolyte disturbances in HNF1β patients remains elusive. Systematic phenotyping of Hnf1b mouse models and the development of patient-specific kidney organoid models will be essential to advance future HNF1β research.

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Section: Mechanisms Of Disturbed Electrolyte Transport In Adtkd-hnf1β...mentioning

confidence: 99%

Mechanisms of ion transport regulation by HNF1β in the kidney: beyond transcriptional regulation of channels and transporters

Tholen

Hoenderop

Baaij

2022

Pflugers Arch - Eur J Physiol

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“…This channel’s role in cardiovascular diseases is unclear, but it may amplify the effects of HypoMg or even be a primary cause of HypoMg. For example, TRPM6 upregulation may be important when understanding the association between diabetes and HypoMg [ 65 , 96 , 101 , 102 ]. Moreover, TRPM6 phosphorylates TRPM7 [ 103 ] and can, therefore, modulate TRPM7 activity in cardiovascular diseases.…”

Section: Trpm7 May Mediate the Oxidative Stress And Inflammation Of H...mentioning

confidence: 99%

Beyond Ion Homeostasis: Hypomagnesemia, Transient Receptor Potential Melastatin Channel 7, Mitochondrial Function, and Inflammation

Liu,

Dudley

2023

Nutrients

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As the second most abundant intracellular divalent cation, magnesium (Mg2+) is essential for cell functions, such as ATP production, protein/DNA synthesis, protein activity, and mitochondrial function. Mg2+ plays a critical role in heart rhythm, muscle contraction, and blood pressure. A significant decline in Mg2+ intake has been reported in developed countries because of the increased consumption of processed food and filtered/deionized water, which can lead to hypomagnesemia (HypoMg). HypoMg is commonly observed in cardiovascular diseases, such as heart failure, hypertension, arrhythmias, and diabetic cardiomyopathy, and HypoMg is a predictor for cardiovascular and all-cause mortality. On the other hand, Mg2+ supplementation has shown significant therapeutic effects in cardiovascular diseases. Some of the effects of HypoMg have been ascribed to changes in Mg2+ participation in enzyme activity, ATP stabilization, enzyme kinetics, and alterations in Ca2+, Na+, and other cations. In this manuscript, we discuss new insights into the pathogenic mechanisms of HypoMg that surpass previously described effects. HypoMg causes mitochondrial dysfunction, oxidative stress, and inflammation. Many of these effects can be attributed to the HypoMg-induced upregulation of a Mg2+ transporter transient receptor potential melastatin 7 channel (TRMP7) that is also a kinase. An increase in kinase signaling mediated by HypoMg-induced TRPM7 transcriptional upregulation, independently of any change in Mg2+ transport function, likely seems responsible for many of the effects of HypoMg. Therefore, Mg2+ supplementation and TRPM7 kinase inhibition may work to treat the sequelae of HypoMg by preventing increased TRPM7 kinase activity rather than just altering ion homeostasis. Since many diseases are characterized by oxidative stress or inflammation, Mg2+ supplementation and TRPM7 kinase inhibition may have wider implications for other diseases by acting to reduce oxidative stress and inflammation.

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“…TRPM6 is mostly expressed in the kidneys, distal small intestine, and colon [166]. The TRPM6 channel is permeable to magnesium (Mg 2+ ), thus assuming a relevant role in epithelial Mg 2+ transport and active Mg 2+ absorption, especially in the gut and kidneys [167]. Hypomagnesemia is evidenced in cancer patients after cisplatin-based chemotherapies [168], and it has emerged as the most notable adverse effect of the anti-epidermal growth factor receptor (EGFR) monoclonal antibody, cetuximab, which is used widely for the treatment of advanced colorectal cancer cells [169].…”

Section: Trpm6mentioning

confidence: 99%

TRP Channels in Cancer: Signaling Mechanisms and Translational Approaches

Marini,

Titiz,

Souza Monteiro de Araújo

et al. 2023

Biomolecules

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Ion channels play a crucial role in a wide range of biological processes, including cell cycle regulation and cancer progression. In particular, the transient receptor potential (TRP) family of channels has emerged as a promising therapeutic target due to its involvement in several stages of cancer development and dissemination. TRP channels are expressed in a large variety of cells and tissues, and by increasing cation intracellular concentration, they monitor mechanical, thermal, and chemical stimuli under physiological and pathological conditions. Some members of the TRP superfamily, namely vanilloid (TRPV), canonical (TRPC), melastatin (TRPM), and ankyrin (TRPA), have been investigated in different types of cancer, including breast, prostate, lung, and colorectal cancer. TRP channels are involved in processes such as cell proliferation, migration, invasion, angiogenesis, and drug resistance, all related to cancer progression. Some TRP channels have been mechanistically associated with the signaling of cancer pain. Understanding the cellular and molecular mechanisms by which TRP channels influence cancer provides new opportunities for the development of targeted therapeutic strategies. Selective inhibitors of TRP channels are under initial scrutiny in experimental animals as potential anti-cancer agents. In-depth knowledge of these channels and their regulatory mechanisms may lead to new therapeutic strategies for cancer treatment, providing new perspectives for the development of effective targeted therapies.

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Transcriptional Control of Trpm6 by the Nuclear Receptor FXR

Cited by 7 publications

References 77 publications

Mechanisms of ion transport regulation by HNF1β in the kidney: beyond transcriptional regulation of channels and transporters

Mechanisms of ion transport regulation by HNF1β in the kidney: beyond transcriptional regulation of channels and transporters

Beyond Ion Homeostasis: Hypomagnesemia, Transient Receptor Potential Melastatin Channel 7, Mitochondrial Function, and Inflammation

TRP Channels in Cancer: Signaling Mechanisms and Translational Approaches

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