Adrenomedullin-sensitive receptors are preferentially expressed in cultured rat mesangial cells

Osajima, Akihiko; Uezono, Yasuhito; Tamura, Masahito; Kïtamura, Kazuo; Mutoh, Yoshinobu; Ueta, Yoichi; Kangawa, Kenji; Kawamura, Masaru; Eto, Tanenao; Yamashita, Hiroshi; Izumi, Fujio; Takasugi, Masayuki; Kuroiwa, Akio

doi:10.1016/s0014-2999(96)00557-2

Cited by 49 publications

(25 citation statements)

References 21 publications

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“…Rat MC were obtained from the intact glomeruli of 4-week-old Wistar rats prepared by the sieving method previously described by Osajima et al [14]. In brief, MC were grown in DMEM supplemented with 20% FCS, 200 mg/ml penicillin and 100 mg/ml streptomycin at 37°C in a humidified atmosphere of 5% CO 2 in air.…”

Section: Methodsmentioning

confidence: 99%

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

Osajima¹,

Katô²,

Uezono³

et al. 1999

Nephron

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Adrenomedullin (AM), a hypotensive peptide isolated from human pheochromocytoma, inhibits the proliferation of mesangial cells (MC) induced by mitogens such as platelet-derived growth factor. Quite recently, we have demonstrated that transmural pressure applied to cultured MC increased DNA synthesis and cell proliferation through protein kinase C and tyrosine kinase pathways. However, the modulatory effect of AM on pressure-induced cell proliferation is as yet unknown. In the present study, we examined the effect of AM on transmural pressure-induced DNA synthesis in cultured rat MC. Pressure was applied to cells placed in a sealed chamber using compressed helium. Application of pressure resulted in an increase in [³H]thymidine incorporation (approximately 2.0-fold). AM clearly inhibited pressure-induced DNA synthesis in a concentration-dependent manner. This inhibition was paralleled by an increase in cellular cAMP levels evoked by AM. Forskolin and dibutyryl cAMP mimicked the inhibitory effect of AM. The protein kinase A inhibitor H-89 significantly attenuated the effect of AM. Human AM(22–52)-NH₂, a putative AM receptor antagonist, reversed the inhibitory effects of AM more potently than did human CGRP(8–37), a calcitonin gene related peptide receptor antagonist. Our results suggest that AM, by acting mainly on AM-sensitive receptors, inhibits pressure-induced DNA synthesis in cultured rat MC through activation of protein kinase A. AM may play a protective role against MC proliferation in certain pathological conditions.

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Section: Methodsmentioning

confidence: 99%

“…The cAMP assay was performed as described previously [14]. Briefly, cells were washed with ice-cold PBS (pH 7.4) and incubated at 37°C for 10 min with or without varying amounts of AM in 1 ml of PBS buffer (pH 7.4) containing 0.5 m M IBMX.…”

Section: Methodsmentioning

confidence: 99%

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

Osajima¹,

Katô²,

Uezono³

et al. 1999

Nephron

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“…[1][2][3][4] The AM infusion studies revealed that AM increased renal blood flow, urine flow, and urinary sodium excretion (UNaV) and decreased proximal and distal fractional reabsorption of sodium. [5][6][7][8][9] Furthermore, AM has been shown to inhibit DNA synthesis 10,11 and endothelin production 12 and to stimulate cAMP formation 13 in mesangial cells and renal tubular cells. 14,15 These findings suggest that AM may elicit its action as an autocrine and/or a paracrine factor as well as a circulating factor in the kidney.…”

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confidence: 99%

Alterations of Intrarenal Adrenomedullin and Its Receptor System in Heart Failure Rats

et al. 2001

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Abstract-Calcitonin receptor-like receptor/receptor activity-modifying protein 2 (CRLR/RAMP2) and CRLR/RAMP3 complexes have been reported to be specific adrenomedullin (AM) receptors. In the present study, we evaluated the pathophysiological significance of renal AM and its receptor system in aortocaval shunt (ACS) rats. Renal AM levels were measured serially during 5 weeks after the operation. Renal gene expressions of AM, CRLR, RAMP2, and RAMP3 were measured at 2 weeks (decompensated phase) and 5 weeks (compensated phase) after the operation. Immunohistochemical localizations of renal AM were also evaluated. Furthermore, the relations between urinary sodium excretion (UNaV) and renal AM levels were evaluated. Renal AM levels were higher in ACS than in control animals only at 1, 2, and 3 weeks after the operation. At 2 weeks after the operation, renal AM mRNA expression was also higher in ACS than in control animals. CRLR, RAMP2, and RAMP3 mRNAs were expressed in the kidney, but there were no differences between the 2 groups. Immunohistochemistry revealed the positive AM immunostaining within the renal tubular cells, and it was more intense in ACS than in control animals. There were significant correlations between UNaV and renal AM levels. At 5 weeks after the operation, there were no differences in mRNA levels of AM, CRLR, RAMP2, and RAMP3 between the 2 groups. There was a significant correlation between UNaV and medullary AM levels. The present findings suggest that increased renal AM levels in decompensated heart failure, presumably due to increased AM production in renal tubules, in part, are involved in the regulation of sodium excretion. Key Words: adrenomedullin Ⅲ receptors, adrenomedullin Ⅲ kidney Ⅲ heart failure Ⅲ sodium A drenomedullin (AM) and its gene expression have been reported to be observed in the glomerulus, distal tubules, and medullary collecting duct cells with respect to limitation to the kidney. [1][2][3][4] The AM infusion studies revealed that AM increased renal blood flow, urine flow, and urinary sodium excretion (UNaV) and decreased proximal and distal fractional reabsorption of sodium. 5-9 Furthermore, AM has been shown to inhibit DNA synthesis 10,11 and endothelin production 12 and to stimulate cAMP formation 13 in mesangial cells and renal tubular cells. 14,15 These findings suggest that AM may elicit its action as an autocrine and/or a paracrine factor as well as a circulating factor in the kidney. However, the specific AM receptor that mediates these many AM functions was only recently elucidated. McLatchie et al 16 demonstrated that the calcitonin receptor-like receptor (CRLR), a receptor with 7 transmembrane domains, can function as either a calcitonin gene-related peptide (CGRP) receptor or an AM receptor, depending on which members of a new family of single-transmembrane-domain proteins, which are called receptor-activity-modifying proteins (RAMPs) are expressed. RAMP1 presents the receptor at the cell surface as a CGRP receptor, whereas RAMP2-or RAMP3-transported receptors ...

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“…In the present study using isolated guinea pig atrium preparations, CGRP (1 -37), a full agonist of CGRP 1 -like receptor, was found to act selectively as a potent stimulator of chronotropic action. Furthermore, CGRP (8 -37), an antagonist of CGRP 1 -type receptors, significantly inhibited 5-HT-induced tachycardia under our experimental conditions, while adrenomedullin (22 -52), an antagonist of adrenomedullin receptors that was suggested to have some interactions with CGRP (1 -37) (19), showed no such effect. These results strongly suggested that the 5-HTinduced positive chronotropic effect can be elicited by release of bioactive peptide, i.e., CGRP, from capsaicinsensitive pools in a ruthenium red-sensitive manner.…”

Section: Discussionmentioning

confidence: 53%

5-HT-Induced, 5-HT3 Receptor-Mediated, and Ruthenium Red-and Capsaicin-Sensitive Positive Chronotropic Effects in the Isolated Guinea Pig Atrium

Nishio

Morimoto

Hisaoka

et al. 2002

Japanese Journal of Pharmacology

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ABSTRACT-We investigated the mechanisms of 5-HT-induced tachycardia, which we reported previously to be triggered by 5-HT3 receptor stimulation, in the isolated guinea pig atrium in comparison with that induced by isoproterenol and histamine. We found that 5-HT-induced tachycardia was completely inhibited by ruthenium red. 5-HT-induced tachycardia was reduced in the capsaicin pre-treated atrium as well as in the presence of capsaicin. The effects of isoproterenol and histamine were not affected by ruthenium red or capsaicin treatment. Furthermore, 5-HT-induced tachycardia was found to be potentiated by thiorphan, an inhibitor of peptide degeneration. Calcitonin gene-related peptide (CGRP) (1 -37), a full agonist of CGRP 1 -like receptors, was found to act selectively as a potent stimulator of chronotropic action. CGRP (8 -37), an antagonist of CGRP 1 -type receptors, inhibited 5-HT-induced tachycardia as well as effects induced by CGRP (1 -37). The observation that tetrodotoxin failed to affect 5-HT-induced tachycardia excluded the involvement of 5-hydroxytryptaminergic interneurons. Thus, we confirmed that the mechanism of 5-HTinduced tachycardia is distinct from that induced by isoproterenol and histamine. In conclusion, the activation of 5-HT 3 receptors on the sensory nerve terminals brought about ruthenium red-sensitive Ca 2+ influx and resulted in the release of CGRP from capsaicin-sensitive stores, and then CGRP stimulated CGRP 1 -like receptors to produce 5-HT-induced tachycardia.

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Adrenomedullin-sensitive receptors are preferentially expressed in cultured rat mesangial cells

Cited by 49 publications

References 21 publications

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

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

Alterations of Intrarenal Adrenomedullin and Its Receptor System in Heart Failure Rats

5-HT-Induced, 5-HT3 Receptor-Mediated, and Ruthenium Red-and Capsaicin-Sensitive Positive Chronotropic Effects in the Isolated Guinea Pig Atrium

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