The mineralocorticoid receptor-p38MAPK-NFκB or ERK-Sp1 signal pathways mediate aldosterone-stimulated inflammatory and profibrotic responses in rat vascular smooth muscle cells

Zhu, Chuan Jiang; Wang, Qing Qing; Zhou, Jun Lan; Liu, Han Zhi; Hua, Fang; Yang, Hong Zhen; Hu, Zhuo Wei

doi:10.1038/aps.2012.36

Cited by 34 publications

(22 citation statements)

References 18 publications

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“…As detailed below, activation of MR impacts on VSMC through ion channel regulation (McCurley et al, 2012;Tarjus et al, 2015a). MR activation in VSMC induces the expression of profibrotic markers (Jaffe and Mendelsohn, 2005;Kiyosue et al, 2011;Zhu et al, 2012;Calvier et al, 2013).…”

Section: B Role Of the Vascular Smooth Muscle Mineralocorticoid Recementioning

confidence: 99%

Emerging Roles of the Mineralocorticoid Receptor in Pathology: Toward New Paradigms in Clinical Pharmacology

2015

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Section: B Role Of the Vascular Smooth Muscle Mineralocorticoid Recementioning

confidence: 99%

Emerging Roles of the Mineralocorticoid Receptor in Pathology: Toward New Paradigms in Clinical Pharmacology

2015

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“…Expression and activity of Orai1 are up-regulated by the transcription [23]. Regulators of neralocorticoids [24,25]. In patients with non-ischemic cardiac disease and early chronic kidney disease high FGF23 plasma levels are associated with high plasma aldosterone concentrations [11].…”

Section: Introductionmentioning

confidence: 99%

Up-regulation of FGF23 release by aldosterone

Zhang

Umbach

Chen

et al. 2016

Biochemical and Biophysical Research Communications

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The fibroblast growth factor (FGF23) plasma level is high in cardiac and renal failure and is associated with poor clinical prognosis of these disorders. Both diseases are paralleled by hyperaldosteronism. Excessive FGF23 levels and hyperaldosteronism are further observed in Klotho-deficient mice. The present study explored a putative aldosterone sensitivity of Fgf23 transcription and secretion the putative involvement of the aldosterone sensitive serum glucocorticoid inducible kinase SGK1, SGK1 sensitive transcription factor NFB and store operated Ca(2+) entry (SOCE). Serum FGF23 levels were determined by ELISA in mice following sham treatment or exposure to deoxycorticosterone acetate (DOCA) or salt depletion. In osteoblastic UMR106 cells transcript levels were quantified by qRT-PCR, cytosolic Ca(2+) concentration utilizing Fura-2-fluorescence, and SOCE from Ca(2+) entry following store depletion by thapsigargin. As a result, DOCA treatment and salt depletion of mice elevated the serum C-terminal FGF23 concentration. In UMR106 cells aldosterone enhanced and spironolactone decreased SOCE. Aldosterone further increased Fgf23 transcript levels in UMR106 cells, an effect reversed by mineralocorticoid receptor blockers spironolactone and eplerenone, SGK1 inhibitor EMD638683, NFB-inhibitor withaferin A, and Ca(2+) channel blocker YM58483. In conclusion, Fgf23 expression is up-regulated by aldosterone, an effect sensitive to SGK1, NFB and store-operated Ca(2+) entry. AbstractThe fibroblast growth factor (FGF23) plasma level is high in cardiac and renal failure and is associated with poor clinical prognosis of these disorders. Both diseases are paralleled with hyperaldosteronism. Excessive FGF23 levels and hyperaldosteronism are further observed in Klotho-deficient mice. The present study explored a putative aldosterone sensitivity of Fgf23 transcription and secretion and the putative involvement of the aldosterone sensitive serum & glucocorticoid inducibe kinase SGK1 and SGK1 sensitive and store operated Ca 2+ entry (SOCE). Serum FGF23 levels were determined by ELISA in mice following sham treatment or exposure to deoxycorticosterone acetate (DOCA) or salt depletion. In osteoblastic UMR106 cells transcript levels were quantified by qRT-PCR, cytosolic Ca 2+ concentration utilizing Fura-2-fluorescence, and SOCE from Ca 2+ entry following store depletion by thapsigargin. As a result, DOCA treatment and salt depletion of mice elevated the serum C-terminal FGF23 concentration. In UMR106 cells aldosterone enhanced and spironolactone decreased SOCE. Aldosterone further increased Fgf23 transcript levels in UMR106 cells, an effect reversed by mineralocorticoid receptor blockers spironolactone and eplerenone, SGK1 inhibitor EMD638683, -inhibitor withaferin A, and Ca 2+ channel blocker YM58483. In conclusion, Fgf23 expression is up-regulated by aldosterone, an effect sensitive to SGK1, and store-operated Ca 2+ entry.

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“…Regulators of NFκB include mineralocorticoids [33,34]. In patients with non-ischemic cardiac disease and early chronic kidney disease high FGF23 plasma levels are associated with high plasma aldosterone concentrations [17].…”

Section: Introductionmentioning

confidence: 99%

NFκB-sensitive Orai1 expression in the regulation of FGF23 release

et al. 2015

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Fibroblast growth factor (FGF23) plasma levels are elevated in cardiac and renal failure and correlate with poor clinical prognosis of those disorders. Both disorders are associated with inflammation and activation of the inflammatory transcription factor NFB. An excessive FGF23 level is further observed in Klotho-deficient mice. The present study explored a putative sensitivity of FGF23 expression to transcription factor NFB, which is known to upregulate Orai1, the Ca(2+) channel accomplishing storeoperated Ca(2+) entry (SOCE). In osteoblastic cells (UMR106) and immortalized primary periosteal (IPO) cells, protein abundance was determined by Western blotting, and in UMR106 cells, transcript levels were quantified by RT-PCR, cytosolic Ca(2+) activity utilizing Fura-2-fluorescence, and SOCE from Ca(2+) entry following store depletion by thapsigargin. As a result, UMR106 and IPO cells expressed Ca(2+) channel Orai1. SOCE was lowered by NFB inhibitor wogonin as well as by Orai1 inhibitors 2-APB and YM58483. UMR106 cell Fgf23 transcripts were increased by stimulation of SOCE and Ca(2+) ionophore ionomycin and decreased by Orai inhibitors 2-APB, YM58483 and SKF96365, by Orai1 silencing, as well as by NFB inhibitors wogonin, withaferin A, and CAS 545380-34-5. In conclusion, Fgf23 expression is upregulated by stimulation of NFB-sensitive, store-operated Ca(2+) entry. KEY MES-SAGES Osteoblast UMR106 and IPO cells express Ca(2+) channel Orai1. Osteoblast store-operated Ca(2+) entry is accomplished by NFB-sensitive Orai1. Osteoblast Fgf23 transcription is upregulated by increase in the cytosolic Ca(2+) activity.

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The mineralocorticoid receptor-p38MAPK-NFκB or ERK-Sp1 signal pathways mediate aldosterone-stimulated inflammatory and profibrotic responses in rat vascular smooth muscle cells

Cited by 34 publications

References 18 publications

Emerging Roles of the Mineralocorticoid Receptor in Pathology: Toward New Paradigms in Clinical Pharmacology

Emerging Roles of the Mineralocorticoid Receptor in Pathology: Toward New Paradigms in Clinical Pharmacology

Up-regulation of FGF23 release by aldosterone

NFκB-sensitive Orai1 expression in the regulation of FGF23 release

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