Inhibitory Effect of Adrenomedullin on Rat Mesangial Cell Mitogenesis

Segawa, Keiko; Minami, Kouichiro; Sata, Takeyoshi; Kuroiwa, Akio; Shigematsu, Akio

doi:10.1159/000189455

Cited by 45 publications

(28 citation statements)

References 6 publications

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“…AM stimulates cell proliferation in zona glomerulosa cells, skin fibroblasts and keratinocytes (Albertin et al 2003), gliobastoma, lung cancer cells, and endometrial tumors (Oehler et al 2002). Cell growth is inhibited by AM in myocytes, cardiac fibroblasts, vascular smooth muscle cells, prostate cancer cells (Abasolo et al 2004), and mesangial cells (Segawa et al 1996). This discrepancy in biological function might be related to varying cell-type-specific differences in signal transduction pathways.…”

Section: K9mentioning

confidence: 99%

Adrenomedullin increases the expression of calcitonin-like receptor and receptor activity modifying protein 2 mRNA in human microvascular endothelial cells

Schwarz¹,

Renshaw²,

Kapas³

et al. 2006

Journal of Endocrinology

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Adrenomedullin (AM) is a multifunctional peptide hormone, which plays a significant role in vasodilation and angiogenesis, implicating it in hypertension as well as in carcinogenesis. AM exerts its effects via the calcitonin receptor-like receptor (CRLR, now known as CL) complexed with either receptor activity modifying protein (RAMP) 2 or 3. We have investigated the effect of AM on immortalized human microvascular endothelial cells 1, since endothelial cells are a major source as well as a target of AM actions in vivo. Cells treated with AM showed elevated cAMP in a time (5-45 min)-dependent and dose (10 K6 -10 K14 M)-dependent manner. Pre-treatment with the AM receptor antagonist AM 22-52 partially suppressed the AM-induced increase in cAMP levels. An increase in extracellular signal-regulated kinase 1/2 phosphorylation was observed after 5 min of treatment with 10 K8 M AM. This phosphorylation was specific, since we were able to block the AM-induced effect with 1 mM U0126, a specific mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitor. Using realtime PCR, we were able to show for the first time that AM upregulates peptide and mRNA expression of vascular endothelial growth factor (VEGF). However, AM treatment of cells did not result in increased cell proliferation. Instead, we observed that AM and VEGF induced cell migration, which could be inhibited by the AM 22-52 and anti-VEGF antibody respectively. AM also significantly elevated mRNA levels of CL (after 2 and 24 h treatment) and RAMP2 (after 1 and 24 h treatment). The upregulation of the AM receptor at two time points reflects possibly different cellular responses to short-and long-term exposure to AM.

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Section: K9mentioning

confidence: 99%

Adrenomedullin increases the expression of calcitonin-like receptor and receptor activity modifying protein 2 mRNA in human microvascular endothelial cells

Schwarz¹,

Renshaw²,

Kapas³

et al. 2006

Journal of Endocrinology

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“…1,5 In addition, cultured endothelial cells (ECs) and vascular smooth muscle cells of different species have been shown to produce and secrete ADM. 6 ADM is multifunctional in nature, regulating the proliferation, differentiation and migration of a number of different cell lines in addition to exerting its regulatory actions on blood pressure, water and electrolyte balance. [7][8][9][10][11][12][13] Some additional aspects of ADM, such as its growth-promoting and anti-apoptotic capabilities, its angiogenic potential and its up-regulation under hypoxic conditions, suggest that ADM may be an important factor in carcinogenesis. 14,15 ADM exerts growth-promoting effects on neoplasms indirectly via angiogenesis.…”

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confidence: 99%

Adrenomedullin is induced by hypoxia and enhances pancreatic cancer cell invasion

Keleg

Kayed

Jiang

et al. 2007

Intl Journal of Cancer

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Adrenomedullin (ADM) is synthesized by different types of cells and acts by binding calcitonin receptor-like receptor (CRLR) and members of the receptor activity-modifying protein (RAMP) family. In this study, the expression and functional role of ADM and its signaling components were investigated in pancreatic adenocarcinoma (PDAC). By QRT-PCR, median mRNA levels of ADM and CRLR were 1.5-and 2.4-fold higher, respectively, in PDAC tissues compared to normal pancreatic tissues. By immunohistochemistry, ADM, CRLR, RAMP1 and RAMP2, but not RAMP3, were expressed in pancreatic cancer cells. ADM serum levels were significantly increased in PDAC patients compared to healthy controls and chronic pancreatitis (CP) patients, with an area under the ROC curve of 0.83 and 0.98, respectively. At a cut-off level of 30.6 ng/ml, the specificity of ADM to differentiate PDAC from controls and CP patients was 85.5 and 83.6%, with a sensitivity of 80 and 100%. All 5 evaluated pancreatic cancer cells lines expressed ADM, CRLR, RAMP1 and RAMP2, whereas RAMP3 was expressed in only 1/5 pancreatic cancer cell lines. ADM was strongly induced by hypoxia and significantly increased invasiveness in 3/5 human pancreatic cancer cells. Blocking of CRLR decreased invasiveness in 4/5 human pancreatic cancer cells. In addition, rADM slightly up-regulated vascular endothelial growth factor secretion in 3/5 cell lines. In conclusion, ADM is induced by hypoxia and over-expressed in PDAC and might therefore serve as a potential tumor marker. Furthermore, ADM increases invasiveness of some pancreatic cancer cells and might influence angiogenesis, suggesting that blocking this pathway might have a therapeutic potential. ' 2007 Wiley-Liss, Inc.Key words: pancreatic cancer; hypoxia; invasion; calcitonin receptorlike receptor; transforming growth factor-beta Adrenomedullin (ADM) is a peptide that was originally isolated from human pheochromocytoma tissues.1 It consists of 52 amino acids, and shares homology with the calcitonin gene-related peptide (CGRP) and amylin.1 ADM derives from the post-translational proteolytic cleavage of pro-ADM, the last step of which involves the conversion of inactive ADM to active ADM by the peptidyl-glycine alpha-amidating monooxygenase. ADM acts by binding calcitonin receptor-like receptor (CRLR), whose interaction with the subtypes 2 and 3 of a family of receptor activitymodifying proteins (RAMP) gives rise to 2 distinct ADM receptors, named ADM1 (CRLR/RAMP2) and ADM2 (CRLR/ RAMP3) receptors, whereas interaction of RAMP1 with CRLR leads to the formation of the so-called calcitonin gene-related peptide receptor. 2-4High levels of ADM have been found in the human adrenal medulla, heart, lung, kidney and pancreas, as well as in pheochromocytoma tissues. 1,5 In addition, cultured endothelial cells (ECs) and vascular smooth muscle cells of different species have been shown to produce and secrete ADM.6 ADM is multifunctional in nature, regulating the proliferation, differentiation and migration of a number of different cell lines...

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“…In rat mesangial cells, adrenomedullin inhibits mitogenesis even under quiescence and suppresses MAPK activity (52,53). In cultured neonatal rat cardiocytes and cardiac fibroblasts, adrenomedullin suppresses cell growth (54,55).…”

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confidence: 99%