Role of angiotensin II-induced cAMP in mesangial TNF-alpha production.
Previous findings indicated that cAMP had an inhibitory effect of on tumour necrosis factor (TNF)-alpha production. Angiotensin II (Ang II) may activate the cAMP-protein kinase A (PKA) pathway in renal mesangial cells through synthesis of prostaglandins (PGs) and the possibility arises that inhibition of Ang II-induced cAMP formation might result in the overproduction of TNF-alpha in the cell and this hypothesis was tested in the present study. Rat mesangial cells were exposed to Ang II in the presence or absence of cyclooxygenase inhibitor (indomethacin) or cAMP-PKA inhibitor (H-89). Exposure of mesangial cell to Ang II (10(-6)M-10(-8)M) significantly increased intracellular cAMP level through type 1 Ang II receptor but had no effect on TNF-alpha protein release, transcriptional activity, or mRNA. However, following the addition of indomethacin or H-89, Ang II significantly increased TNF-alpha release, transcriptional activity, and mRNA level. These data suggested that in mesangial cells after blockade of cAMP-PKA by PG inhibition, Ang II was capable of stimulating TNF-alpha transcription which subsequently increased TNF-alpha mRNA accumulation and protein release.
Department of Pediatrics, Teikyo University School of Medicine, Tokyo, 173, Japan. akio@med.teikyo-u.ac.jp
Akio
A
Nakamura
Edward J
EJ
Johns
Akira
A
Imaizumi
Ryo
R
Niimi
Yukishige
Y
Yanagawa
Takao
T
Kohsaka
D000804:Angiotensin II / Q000502:physiology*; D000818:Animals; D015152:Blotting, Northern; D000242:Cyclic AMP / Q000378:metabolism*; D017930:Genes, Reporter; D005920:Glomerular Mesangium / Q000473:pathology; D007213:Indomethacin / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D011453:Prostaglandins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D013449:Sulfonamides; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000378:metabolism
D007546:Isoquinolines; D011453:Prostaglandins; D012333:RNA, Messenger; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; D000804:Angiotensin II; D000242:Cyclic AMP; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; D007213:Indomethacin