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Extracellular 3',5'-cAMP-adenosine pathway inhibits glomerular mesangial cell growth


Dubey, R K; Rosselli, M; Gillespie, D G; Mi, Z; Jackson, E K (2010). Extracellular 3',5'-cAMP-adenosine pathway inhibits glomerular mesangial cell growth. Journal of Pharmacology and Experimental Therapeutics, 333(3):808-815.

Abstract

Abnormal growth of glomerular mesangial cells (GMCs) contributes to the pathophysiology of many types of nephropathy. Because adenosine is an autocrine/paracrine factor that potentially could regulate GMC proliferation and because the extracellular 3',5'-cAMP-adenosine pathway (i.e., the conversion of extracellular 3',5'-cAMP to 5'-AMP and adenosine on the cell surface) could generate adenosine in the biophase of GMC receptors, we investigated the role of the 3',5'-cAMP-adenosine pathway in modulating growth [cell proliferation, DNA synthesis ([(3)H]thymidine incorporation), collagen synthesis ([(3)H]proline incorporation), and mitogen-activated protein kinase activity] of GMCs. The addition of exogenous 3',5'-cAMP to human GMCs increased extracellular levels of 5'-AMP, adenosine, and inosine, and 3-isobutyl-1-methylxanthine (phosphodiesterase inhibitor), 1,3-dipropyl-8-p-sulfophenylxanthine (ecto-phosphodiesterase inhibitor), and alpha,beta-methylene-adenosine-5'-diphosphate (ecto-5'-nucleotidase inhibitor) attenuated the increases in adenosine and inosine. Forskolin augmented extracellular 3',5'-cAMP and adenosine concentrations, and 2',5'-dideoxyadenosine (adenylyl cyclase inhibitor) blocked these increases. Exogenous 3',5'-cAMP and forskolin inhibited all indices of cell growth, and antagonism of A(2) [(E)-8-(3,4-dimethoxystyryl)-1,3-dipropyl-7-methylxanthine, KF17837] or A(1)/A(2) (1,3-dipropyl-8-p-sulfophenylxanthine, DPSPX), but not A(1) (8-cyclopentyl-1,3-dipropylxanthine), or A(3){N-(2-methoxyphenyl)-N'-[2-(3-pyridinyl)-4-quinazolinyl]-urea, VUF5574}, adenosine receptors blocked the growth-inhibitory actions of exogenous 3',5'-cAMP, but not the effects of 8-bromo-3',5'-cAMP (stable 3',5'-cAMP analog). Erythro-9-(2-hydroxy-3-nonyl)adenine (adenosine deaminase inhibitor) plus 5-iodotubercidin (adenosine kinase inhibitor) enhanced the growth inhibition by exogenous 3',5'-cAMP and forskolin, and A(2) receptor antagonism blocked this effect. In rat GMCs, down-regulation of A(2B) receptors with antisense, but not sense or scrambled, oligonucleotides abrogated the inhibitory effects of 3',5'-cAMP and forskolin on cell growth. The extracellular 3',5'-cAMP-adenosine pathway exists in GMCs and attenuates cell growth via A(2B) receptors. Pharmacological augmentation of this pathway could abate pathological glomerular remodeling.

Abstract

Abnormal growth of glomerular mesangial cells (GMCs) contributes to the pathophysiology of many types of nephropathy. Because adenosine is an autocrine/paracrine factor that potentially could regulate GMC proliferation and because the extracellular 3',5'-cAMP-adenosine pathway (i.e., the conversion of extracellular 3',5'-cAMP to 5'-AMP and adenosine on the cell surface) could generate adenosine in the biophase of GMC receptors, we investigated the role of the 3',5'-cAMP-adenosine pathway in modulating growth [cell proliferation, DNA synthesis ([(3)H]thymidine incorporation), collagen synthesis ([(3)H]proline incorporation), and mitogen-activated protein kinase activity] of GMCs. The addition of exogenous 3',5'-cAMP to human GMCs increased extracellular levels of 5'-AMP, adenosine, and inosine, and 3-isobutyl-1-methylxanthine (phosphodiesterase inhibitor), 1,3-dipropyl-8-p-sulfophenylxanthine (ecto-phosphodiesterase inhibitor), and alpha,beta-methylene-adenosine-5'-diphosphate (ecto-5'-nucleotidase inhibitor) attenuated the increases in adenosine and inosine. Forskolin augmented extracellular 3',5'-cAMP and adenosine concentrations, and 2',5'-dideoxyadenosine (adenylyl cyclase inhibitor) blocked these increases. Exogenous 3',5'-cAMP and forskolin inhibited all indices of cell growth, and antagonism of A(2) [(E)-8-(3,4-dimethoxystyryl)-1,3-dipropyl-7-methylxanthine, KF17837] or A(1)/A(2) (1,3-dipropyl-8-p-sulfophenylxanthine, DPSPX), but not A(1) (8-cyclopentyl-1,3-dipropylxanthine), or A(3){N-(2-methoxyphenyl)-N'-[2-(3-pyridinyl)-4-quinazolinyl]-urea, VUF5574}, adenosine receptors blocked the growth-inhibitory actions of exogenous 3',5'-cAMP, but not the effects of 8-bromo-3',5'-cAMP (stable 3',5'-cAMP analog). Erythro-9-(2-hydroxy-3-nonyl)adenine (adenosine deaminase inhibitor) plus 5-iodotubercidin (adenosine kinase inhibitor) enhanced the growth inhibition by exogenous 3',5'-cAMP and forskolin, and A(2) receptor antagonism blocked this effect. In rat GMCs, down-regulation of A(2B) receptors with antisense, but not sense or scrambled, oligonucleotides abrogated the inhibitory effects of 3',5'-cAMP and forskolin on cell growth. The extracellular 3',5'-cAMP-adenosine pathway exists in GMCs and attenuates cell growth via A(2B) receptors. Pharmacological augmentation of this pathway could abate pathological glomerular remodeling.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Center for Integrative Human Physiology
04 Faculty of Medicine > University Hospital Zurich > Clinic for Reproductive Endocrinology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:June 2010
Deposited On:12 Nov 2010 15:04
Last Modified:05 Apr 2016 14:15
Publisher:American Society for Pharmacology and Experimental Therapeutics
ISSN:0022-3565
Publisher DOI:https://doi.org/10.1124/jpet.110.166371
PubMed ID:20194527

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