title: Adrenomedullin inhibits pressure-induced mesangial MCP-1 expression through activation of protein kinase A.
abstract: In glomerular hypertension, monocyte chemoattractant protein-1 (MCP-1) has been implicated in glomerulosclerosis progression. High-pressure load and stretch on mesangial cells (MC) are two major effects of increased glomerular pressure. We previously reported that pressure per se could induce MCP-1 expression in cultured MC, suggesting the involvement of glomerular hypertension in renal disease progression through MCP-1 expression in MC. We also showed that adrenomedullin (AM) inhibited pressure-induced MC proliferation; however, it is not clear whether AM alters pressure-induced mesangial MCP-1 expression. In this study, we examined the effect of AM on pressure-induced MCP-1 expression in cultured rat MC and the mechanism of such action. Using compressed helium, pressure was applied to MC placed in a sealed chamber. AM inhibited pressure-induced MCP-1 mRNA expression, measured by reverse transcribed-polymerase chain reaction (RT-PCR), in a dose-dependent manner. This inhibition was in parallel to an increase in cellular cyclic AMP (cAMP) levels evoked by AM. The effects of forskolin and dibutyryl cAMP mimicked those of AM. Protein kinase A (PKA) inhibitor H-89 significantly weakened the effects of AM. AM significantly reduced the pressure-induced increase in MCP-1 protein in supernatants of cultured MC, measured by enzyme-linked immunosorbent assay (ELISA). Our results suggested that AM inhibits pressure-induced mesangial MCP-1 expression through PKA activation.
authors.affiliation: The Second Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
authors.forename: Masako
authors.initials: M
authors.lastname: Iwamoto
authors.forename: Akihiko
authors.initials: A
authors.lastname: Osajima
authors.forename: Masahito
authors.initials: M
authors.lastname: Tamura
authors.forename: Takeshi
authors.initials: T
authors.lastname: Suda
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ota
authors.forename: Kaori
authors.initials: K
authors.lastname: Kanegae
authors.forename: Yuujiro
authors.initials: Y
authors.lastname: Watanabe
authors.forename: Narutoshi
authors.initials: N
authors.lastname: Kabashima
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Anai
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Nakashima
mesh_terms: D053607:Adrenomedullin; D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D002196:Capillaries / Q000503:physiopathology; D002352:Carrier Proteins / Q000494:pharmacology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004789:Enzyme Activation; D004797:Enzyme-Linked Immunosorbent Assay; D005920:Glomerular Mesangium / Q000378:metabolism*; D006977:Hypertension, Renal / Q000503:physiopathology; D047908:Intracellular Signaling Peptides and Proteins; D007546:Isoquinolines / Q000494:pharmacology; D007678:Kidney Glomerulus / Q000098:blood supply; D010455:Peptides / Q000494:pharmacology* / Q000502:physiology; D011312:Pressure; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides
chemical_list: D002352:Carrier Proteins; D018932:Chemokine CCL2; D047908:Intracellular Signaling Peptides and Proteins; D007546:Isoquinolines; D010455:Peptides; D012333:RNA, Messenger; D013449:Sulfonamides; C015482:protein kinase modulator; D053607:Adrenomedullin; D005576:Colforsin; D003994:Bucladesine; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide