c-Src–Dependent Nongenomic Signaling Responses to Aldosterone Are Increased in Vascular Myocytes From Spontaneously Hypertensive Rats

Callera, Gláucia E.; Montezano, Augusto C.; Yogi, Álvaro; Tostes, Rita C.; He, Ying; Schiffrin, Ernesto L.; Touyz, Rhian M.

doi:10.1161/01.hyp.0000176588.51027.35

Cited by 93 publications

(86 citation statements)

References 46 publications

(47 reference statements)

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“…4A) or the cSRC kinase inhibitor PP2 (100 nmol/liter, Fig. 4A), in accordance with the previously demonstrated EGFR and cSRC dependence of rapid MR signaling (9,15,39). Fig.…”

Section: Resultssupporting

confidence: 90%

EF Domains Are Sufficient for Nongenomic Mineralocorticoid Receptor Actions

Großmann

Freudinger

Mildenberger

et al. 2008

Journal of Biological Chemistry

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The mineralocorticoid receptor (MR) is important for salt homeostasis and reno-cardiovascular pathophysiology. Signaling mechanisms include, besides classical genomic pathways, nongenomic pathways with putative pathophysiological relevance involving the mitogen-activated protein kinases ERK1/2. We determined the MR domains required for nongenomic signaling and their potential to elicit pathophysiological effects in cultured cells under defined conditions. The expression of fulllength human MR or truncated MR consisting of the domains CDEF (MR CDEF ), DEF (MR DEF ), or EF (MR EF ) renders cells responsive for the MR ligand aldosterone with respect to nongenomic ERK1/2 phosphorylation, whereas only full-length MR and MR CDEF conferred genomic responsiveness. ERK1/2 phosphorylation depends on the EGF receptor and cSRC kinase. MR EF expression is sufficient to evoke the aldosterone-induced increase of collagen III levels, similar to full-length MR expression. Our data suggest that nongenomic MR signaling is mediated by the EF domains and present the first proof of principle showing that nongenomic signaling can be sufficient for some pathophysiological effects. The minimum amino acid motif required for nongenomic MR signaling and its importance in various effects have yet to be determined. The mineralocorticoid receptor (MR)2 is usually described as a ligand-inducible transcription factor that controls expression of target genes involved in the regulation of Na ϩ and K ϩ homeostasis as well as blood pressure regulation (1). MR also promotes cardiovascular and renal fibrosis caused by tissue remodeling as well as endothelial dysfunction, independent of its effects on blood pressure or NaCl homeostasis (2-4). The activation of MR modulates the expression of various proteins like the epithelial sodium channel, Na ϩ -K ϩ -ATPase, the SGK kinase, and the EGF receptor (1, 5-7). There is increasing evidence that not all biological effects of MR are mediated by direct DNA binding and control of target gene expression (8, 9). Some actions of MR appear to be the result of a cross-talk with other signaling cascades, such as nongenomic regulation of intracellular calcium (10, 11), protein kinase C, cSRC kinase, EGF receptor (EGFR) activity, or extracellular-regulated kinase (ERK1/2) (12-15). Furthermore, there seems to exist a functional cross-talk between classical and nongenomic actions (9, 16 -18).The classical receptors for estrogen (ER), progesterone (PR), androgens (AR), and glucocorticoids (GR) also contribute to the nongenomic effects (12, 14, 19 -26) of these hormones, in many cases via ERK1/2 kinases. Some nongenomic effects arise from classical receptors in or at the plasma membrane (e.g. ER, Ref. 13) but specialized membrane receptors, like mPR and GPR30 have also been described (27, 28). However, the results for the specialized membrane receptors are controversial (29, 30). The mechanism(s) of action for ER and PR as well as the receptor domains involved have been explored in more detail. Receptor domains D, E, a...

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“…4A) or the cSRC kinase inhibitor PP2 (100 nmol/liter, Fig. 4A), in accordance with the previously demonstrated EGFR and cSRC dependence of rapid MR signaling (9,15,39). Fig.…”

Section: Resultssupporting

confidence: 90%

EF Domains Are Sufficient for Nongenomic Mineralocorticoid Receptor Actions

Großmann

Freudinger

Mildenberger

et al. 2008

Journal of Biological Chemistry

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“…The pathophysiological role of aldosterone in vascular hypertrophy and renal vascular diseases, as well as the potential application of Src or ATF1 blockage to antagonize the clinic vascular injury, warrants further study. that Src is the upstream of Nox1 in the VSMCs aldosterone response, which has already been shown by other groups [31,[33][34]. In this study, we revealed a novel pathway, Src-ATF1, in Nox1 activation and subsequently ROS generation in VSMCs following an aldosterone stimulus.…”

Section: Discussionsupporting

confidence: 83%

Activation of Src-ATF1 pathway is involved in upregulation of Nox1, a catalytic subunit of NADPH oxidase, by aldosterone

et al. 2011

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“…As described above, in addition to the MR-mediated genomic effects of aldosterone, non-genomic effects of aldosterone have also been described (7,8,53,54). Although it has been suggested that the non-genomic effects of aldosterone are mediated via MR (12,55), MR-independent mechanisms have also been reported to mediate the non-genomic effects of aldosterone (53,56).…”

Section: Effects Of Aldosterone/mr On Renal Hemodynamic Parameters Inmentioning

confidence: 96%

“…Aldosterone is classically known to bind to the cytosolic mineralocorticoid receptor (MR) in epithelial cells and aldosterone-bound MR translocates to the nucleus to promote protein synthesis. It has also been suggested that aldosterone, via rapid non-genomic pathways, regulates vasoconstriction (7) and c-Src activation in vascular smooth muscle cells (8). Although intrinsic glucocorticoids (cortisol in human and corticosterone in rodents) also show high affinity to the MR, aldosterone specially induces physiological responses through the MR by 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2)-dependent regulation.…”

Section: Introductionmentioning

confidence: 99%

Pathophysiological Roles of Aldosterone and Mineralocorticoid Receptor in the Kidney

et al. 2011

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Abstract. Aldosterone, a steroid hormone, has traditionally been viewed as a key regulator of fluid and electrolyte homeostasis, as well as blood pressure, through the activation of mineralocorticoid receptor (MR). However, a number of studies performed in the last decade have revealed an important role of aldosterone/MR in the pathogenesis of renal injury. Aldosterone/MR-induced renal tissue injury is associated with increased renal inflammation and oxidative stress, fibrosis, mesangial cell proliferation, and podocyte injury, probably through genomic and non-genomic pathways. However, our preliminary data have indicated that acute administration of aldosterone or a selective MR antagonist, eplerenone, does not change blood pressure, heart rate, or renal blood flow. These data suggest that aldosterone/MR induces renal injury through mechanisms that are independent of acute changes in systemic and renal hemodynamics. In this review, we will briefly summarize the roles of aldosterone/MR in the pathogenesis of renal injury, focusing on the underlying mechanisms that are independent of systemic and renal hemodynamic changes.

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c-Src–Dependent Nongenomic Signaling Responses to Aldosterone Are Increased in Vascular Myocytes From Spontaneously Hypertensive Rats

Cited by 93 publications

References 46 publications

EF Domains Are Sufficient for Nongenomic Mineralocorticoid Receptor Actions

EF Domains Are Sufficient for Nongenomic Mineralocorticoid Receptor Actions

Activation of Src-ATF1 pathway is involved in upregulation of Nox1, a catalytic subunit of NADPH oxidase, by aldosterone

Pathophysiological Roles of Aldosterone and Mineralocorticoid Receptor in the Kidney

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