Cardioprotective Mechanisms of Spironolactone Associated with the Angiotensin-Converting Enzyme/Epidermal Growth Factor Receptor/Extracellular Signal-Regulated Kinases, NAD(P)H Oxidase/Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1, and Rho-Kinase Pathways in Aldosterone/Salt-Induced Hypertensive Rats

Nakano, Shigefumi; Kobayashi, Naohiko; Yoshida, Kenichi; Ohno, Tomoyuki; Matsuoka, Hiroaki

doi:10.1291/hypres.28.925

Cited by 78 publications

(82 citation statements)

References 50 publications

(56 reference statements)

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“…Previously, EGFR signaling has been reported to be affected by several antihypertensive therapies such as renin-angiotensin system inhibitors, endothelin 1 receptor antagonists, and antioxidants (Fujino et al, 1998;Dorrance et al, 2001;Nakano et al, 2005;Portik-Dobos et al, 2006), which matches the observed decrease in pEGFR expression in lisinopril-treated 5/6Nx animals. Moreover, the ACE inhibitor imidapril (Nakano et al, 2005), the AT 1 R antagonist losartan (Lautrette et al, 2005), and the aldosterone antagonist spironolactone ) also affect EGFR signaling.…”

Section: Chronic Egfr Inhibition Prevents Hypertensionsupporting

confidence: 76%

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Epidermal Growth Factor Receptor Inhibitor PKI-166 Governs Cardiovascular Protection without Beneficial Effects on the Kidney in Hypertensive 5/6 Nephrectomized Rats

Ulu

Mulder

Vavrinec

et al. 2013

J Pharmacol Exp Ther

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Transactivation of epidermal growth factor receptor (EGFR) signaling by G protein-coupled receptors has been implicated in several cardiovascular (CV) conditions, including hypertension, heart failure, and cardiac and vascular hypertrophy. However, the therapeutic potential of EGFR inhibition in these conditions is currently unknown. The main objective of the present study was to investigate cardiac, vascular, and renal effects of EGFR inhibition by 4- in the hypertensive chronic kidney disease model. Rats underwent 5/6 nephrectomy (5/ 6Nx) and were treated with PKI-166, lisinopril or vehicle from week 6 after disease induction until week 12. Sham animals received either PKI-166 or vehicle. Treatment with PKI-166 did not affect the development of the characteristic renal features in 5/6Nx, including proteinuria, diminished creatinine clearance, and increased glomerulosclerosis, whereas these were attenuated by lisinopril. Despite absence of effects on progressive renal damage, PKI-166 attenuated the progression of hypertension and maintained cardiac function (left ventricle end-diastolic pressure) to a similar extent as lisinopril. Also, PKI-166 attenuated the increase in phosphorylated EGFR in the heart as induced by 5/6Nx. Moreover, PKI-166 and lisinopril restored the impaired contraction of isolated thoracic aortic rings to phenylephrine and angiotensin II and impaired myogenic constriction of small mesenteric arteries in 5/6Nx rats. Blockade of the EGFR displays a CV benefit independent of limiting the progression of renal injury. Our findings extend the evidence on EGFR signaling as a target in CV disorders.

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Section: Chronic Egfr Inhibition Prevents Hypertensionsupporting

confidence: 76%

“…Moreover, the ACE inhibitor imidapril (Nakano et al, 2005), the AT 1 R antagonist losartan (Lautrette et al, 2005), and the aldosterone antagonist spironolactone ) also affect EGFR signaling. Thus, our observation that PKI-166 treatment successfully lowered blood pressure in …”

Section: Chronic Egfr Inhibition Prevents Hypertensionmentioning

confidence: 99%

Epidermal Growth Factor Receptor Inhibitor PKI-166 Governs Cardiovascular Protection without Beneficial Effects on the Kidney in Hypertensive 5/6 Nephrectomized Rats

Ulu

Mulder

Vavrinec

et al. 2013

J Pharmacol Exp Ther

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“…There is a large body of evidence showing an activation of extracellular signal-related kinase-1/2 in response to many known hypertropic agonists. 48,49 However, Purcell et al 50 have recently shown that extracellular signal-related kinase-1/2 signaling is not required for mediating physiological or pathological cardiac hypertrophy in vivo; moreover, blockade or deletion of cardiac Figure 5 Cluster analysis of genes selectively normalized by QHI in late LVH. The transcripts differentially expressed in late LVH were then filtered to select out those selectively normalized by the QHI treatment group and average linkage hierarchical cluster analysis of this cohort was then performed to graphically illustrate their expression profile.…”

Section: Signal Transductionmentioning

confidence: 99%

Transcriptome of hypertension-induced left ventricular hypertrophy and its regression by antihypertensive therapies

et al. 2009

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Left ventricular hypertrophy (LVH), a common consequence of systemic hypertension associated with poor clinical outcome, is also a potentially reversible condition. Here, we probed the molecular pathways that underpin the development of LVH and their modulation by antihypertensive regimens that reversed LVH. Spontaneously hypertensive rats were studied at 12 (early LVH) and 48 weeks (late LVH), respectively, with normotensive Wistar-Kyoto rats as age-matched controls. Three treatment groups were maintained for 36 weeks on the following regimens: (1) quinapril, (2) doxazosin and quinapril combination, and (3) losartan. Gene expression profiling was performed with Affymetrix microarrays (GeneChip Rat-230A) and primary function-focused average linkage hierarchical cluster analysis. Of the 15 696 gene sequences expressed on the Affymetrix GeneChip Rat-230A, there was significant alteration in the expression of 295 (1.9%) of these transcripts in 'early' LVH and 143 (0.9%) in 'late' LVH. The predominant changes in gene expression were seen in metabolism, cell growth/proliferation, signal transduction, development and muscle contraction/cytoskeleton functional groups. Although sharing many effects on gene expression, the three treatments showed different expression profiles. Despite significant regression of LVH with treatment, 31 LVH-associated transcripts were unchanged by any of the treatment groups. Our data suggest that LVH regression does not normalize the LVH transcriptome. Therefore, regression of hypertension-induced LVH is associated with a distinct gene expression profile, suggesting the effect of both treatment and a previously unknown specific myocardial physiology after regression of LVH.

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“…In the kidney, aldosterone via MR additionally induces mesangial cell proliferation via ROS-dependent activation of EGFR, leading to combined ERK1/2 and PI3K/mTOR signaling ). There is a close interaction between genomic and nongenomic aldosterone signaling because aldosterone/MR can both transactivate the EGFR and enhance its expression (Dorrance et al 2001, Nakano et al 2005, Meinel et al 2013. Furthermore, nongenomic aldosterone-mediated ERK1/2 phosphorylation seems to enhance MR nuclear shuttling and thereby transactivation activity (Grossmann et al 2005).…”

Section: Egfrmentioning

confidence: 99%

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Nongenomic effects via the mineralocorticoid receptor

Ruhs

Nolze

Hübschmann

et al. 2017

Journal of Endocrinology

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The mineralocorticoid receptor (MR) belongs to the steroid hormone receptor family and classically functions as a ligand-dependent transcription factor. It is involved in water-electrolyte homeostasis and blood pressure regulation but independent from these effects also furthers inflammation, fibrosis, hypertrophy and remodeling in cardiovascular tissues. Next to genomic effects, aldosterone elicits very rapid actions within minutes that do not require transcription or translation and that occur not only in classical MR epithelial target organs like kidney and colon but also in nonepithelial tissues like heart, vasculature and adipose tissue. Most of these effects can be mediated by classical MR and its crosstalk with different signaling cascades. Near the plasma membrane, the MR seems to be associated with caveolin and striatin as well as with receptor tyrosine kinases like EGFR, PDGFR and IGF1R and G proteincoupled receptors like AT1 and GPER1, which then mediate nongenomic aldosterone effects. GPER1 has also been named a putative novel MR. There is a close interaction and functional synergism between the genomic and the nongenomic signaling so that nongenomic signaling can lead to long-term effects and support genomic actions. Therefore, understanding nongenomic aldosterone/MR effects is of potential relevance for modulating genomic aldosterone effects and may provide additional targets for intervention.

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Abstract: Studies were performed to test the hypothesis that the angiotensin-converting enzyme (ACE)/

Cited by 78 publications

References 50 publications

Epidermal Growth Factor Receptor Inhibitor PKI-166 Governs Cardiovascular Protection without Beneficial Effects on the Kidney in Hypertensive 5/6 Nephrectomized Rats

Epidermal Growth Factor Receptor Inhibitor PKI-166 Governs Cardiovascular Protection without Beneficial Effects on the Kidney in Hypertensive 5/6 Nephrectomized Rats

Transcriptome of hypertension-induced left ventricular hypertrophy and its regression by antihypertensive therapies

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Nongenomic effects via the mineralocorticoid receptor

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