Adrenomedullin Inhibits Transmural Pressure Induced Mesangial Cell Proliferation through Activation of Protein Kinase A

Osajima, Akihiko; Katô, Hiroaki; Uezono, Yasuhito; Suda, Takafumi; Okazaki, Masahiro; Oishi, Yosuke; Tamura, Masahito; Tanaka, Hiroshi; Izumi, Fujio; Nakashima, Yasuhide

doi:10.1159/000045427

Cited by 17 publications

(9 citation statements)

References 27 publications

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“…AM was originally identified as a peptide that increases cAMP levels in platelets. 1 Subsequent experiments in mesangial cells yielded results similar to those reported herein 30,31 : AM increased cAMP levels, which led to a PKAdependent decrease in cell proliferation that was associated with decreased ERK activity. It was also shown that delivery of the AM gene attenuates cardiac hypertrophy via production of cAMP 32,33 and that AM cAMP-dependently inhibited DNA synthesis and collagen production in cardiac fibroblasts.…”

Section: Discussionsupporting

confidence: 72%

Protective Effects of Endogenous Adrenomedullin on Cardiac Hypertrophy, Fibrosis, and Renal Damage

et al. 2004

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Background-Adrenomedullin (AM) is a novel vasodilating peptide thought to have important effects on cardiovascular function.The aim of this study was to assess the activity of endogenous AM in the cardiovascular system using AM knockout mice. Methods and Results-Mice heterozygous for an AM-null mutation (AMϩ/Ϫ) and their wild-type littermates were subjected to aortic constriction or angiotensin II (Ang II) infusion. The resultant cardiovascular stress led to increases in heart weight/body weight ratios, left ventricular wall thickness, and perivascular fibrosis, as well as expression of genes encoding angiotensinogen, ACE, transforming growth factor-␤, collagen type I, brain natriuretic peptide, and c-fos. In addition, renal damage characterized by decreased creatinine clearance with glomerular sclerosis was noted. In all cases, the effects were significantly more pronounced in AMϩ/Ϫ mice. Hearts from adult mice subjected to aortic constriction showed enhanced extracellular signal-regulated kinase (ERK) activation, as did cardiac myocytes from neonates treated acutely with Ang II. Again the effect was more pronounced in AMϩ/Ϫ mice, which showed increases in cardiac myocyte size, protein synthesis, and fibroblast proliferation. ERK activation was suppressed by protein kinase C inhibition to a greater degree in AMϩ/Ϫ myocytes. In addition, treatment of cardiac myocytes with recombinant AM suppressed Ang II-induced ERK activation via a protein kinase A-dependent pathway. Conclusions-Endogenous AM exerts a protective effect against stress-induced cardiac hypertrophy via protein kinase Cand protein kinase A-dependent regulation of ERK activation. AM may thus represent a useful new tool for the treatment of cardiovascular disease.

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Section: Discussionsupporting

confidence: 72%

Protective Effects of Endogenous Adrenomedullin on Cardiac Hypertrophy, Fibrosis, and Renal Damage

et al. 2004

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“…The intracellular signaling mechanism of AM appears to be cAMP, 29,30 Ca 2ϩ mobilization, 31 inositol-1,4,5-triphosphate, 32 protein kinase A, 33 and mitogen-activated protein kinase pathways. 34 However, there are few reports about the signaling pathways of the suppressive effect of AM on the expression of endothelial adhesion molecules.…”

Section: Discussionmentioning

confidence: 99%

Adrenomedullin Reduces VEGF-Induced Endothelial Adhesion Molecules and Adhesiveness Through a Phosphatidylinositol 3′-Kinase Pathway

Kim

Moon

Lee

et al. 2003

ATVB

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Objective-In the initial phase of inflammation, vascular endothelial growth factor (VEGF) can act as a proinflammatory cytokine by inducing adhesion molecules that bind leukocytes to endothelial cells. Adrenomedullin (AM) is known to act as either a proinflammatory or an anti-inflammatory agent. In this study, we examined the effects of AM on adhesion molecule expression and leukocyte adhesiveness in VEGF-stimulated human umbilical vein endothelial cells. Methods and Results-When stimulated with VEGF, the mRNAs of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin were dose-dependently upregulated. AM inhibited the VEGFinduced protein and mRNA expression of ICAM-1, VCAM-1, and E-selectin. Phosphatidylinositol 3Ј-kinase inhibitor and a dominant-negative form of Akt significantly inhibited the suppressive effect of AM on VEGF-induced adhesion molecule expression. Thus, AM inhibits VEGF-stimulated ICAM-1 and VCAM-1 expression through a phosphatidylinositol 3Ј-kinase/Akt pathway. AM reduced VEGF-induced endothelial adhesiveness for leukocytes. Conclusions-These

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“…To determine whether AM/AMBP-1 reconstitutes LPS-induced reduction in PPAR-␥ expression, RAW264.7 macrophages were coincubated with AM/AMBP-1 at different concentrations (100 -200 nM AM and 50 -100 nM AMBP-1) based on previous reports (28,29). Four hours of incubation induced a significant increase in PPAR-␥ mRNA expression (Fig.…”

Section: Lps-mediated Inhibition Of Ppar-␥ Expression Is Reconstitutementioning

confidence: 96%

Vasoactive Hormone Adrenomedullin and Its Binding Protein: Anti-Inflammatory Effects by Up-Regulating Peroxisome Proliferator-Activated Receptor-γ

Miksa

Cui

et al. 2007

The Journal of Immunology

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Sepsis is a critical inflammatory condition from which numerous patients die due to multiple organ failure and septic shock. The vasoactive hormone adrenomedullin (AM) and its binding protein (AMBP-1) are beneficial in sepsis by abrogating the progression to irreversible shock and decreasing proinflammatory cytokine release. To investigate the anti-inflammatory mechanism, we studied to determine the effect of the AM/AMBP-1 complex on peroxisome proliferator-activated receptor-γ (PPAR-γ) expression and activation by using RAW264.7 cells and a rat endotoxemia model. LPS treatment significantly decreased PPAR-γ expression in vivo and in vitro and was associated with increased TNF-α production. Treatment with AM/AMBP-1 for 4 h completely restored PPAR-γ levels in both models, resulting in TNF-α suppression. In a knockdown model using small interfering RNA in RAW264.7 macrophages, AM/AMBP-1 failed to suppress TNF-α production in the absence of PPAR-γ. LPS caused the suppression of intracellular cyclic AMP (cAMP), which was prevented by simultaneous AM/AMBP-1 treatment. Although incubation with dibutyryl cAMP significantly decreased LPS-induced ΤΝF-α release, it did not alter PPAR-γ expression. Through inhibition studies using genistein and PD98059 we found that the Pyk-2 tyrosine kinase-ERK1/2 pathway is in part responsible for the AM/AMBP-1-mediated induction of PPAR-γ and the anti-inflammatory effect. We conclude that AM/AMBP-1 is protective in sepsis due to its vasoactive properties and direct anti-inflammatory effects mediated through both the cAMP-dependent pathway and Pyk-2-ERK1/2-dependent induction of PPAR-γ.

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Adrenomedullin Inhibits Transmural Pressure Induced Mesangial Cell Proliferation through Activation of Protein Kinase A

Cited by 17 publications

References 27 publications

Protective Effects of Endogenous Adrenomedullin on Cardiac Hypertrophy, Fibrosis, and Renal Damage

Protective Effects of Endogenous Adrenomedullin on Cardiac Hypertrophy, Fibrosis, and Renal Damage

Adrenomedullin Reduces VEGF-Induced Endothelial Adhesion Molecules and Adhesiveness Through a Phosphatidylinositol 3′-Kinase Pathway

Vasoactive Hormone Adrenomedullin and Its Binding Protein: Anti-Inflammatory Effects by Up-Regulating Peroxisome Proliferator-Activated Receptor-γ

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