Adrenomedullin inhibits pressure-induced mesangial MCP-1 expression through activation of protein kinase A.
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.
Iwamoto
Masako
M
The Second Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
Osajima
Akihiko
A
Tamura
Masahito
M
Suda
Takeshi
T
Ota
Takayuki
T
Kanegae
Kaori
K
Watanabe
Yuujiro
Y
Kabashima
Narutoshi
N
Anai
Hirofumi
H
Nakashima
Yasuhide
Y
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
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