Bradykinin inhibits ceramide production and activates phospholipase D in rabbit cortical collecting duct cells.
Recent reports suggest that inflammatory cytokines, growth factors, and vasoconstrictor peptides induce sphingomyelinase (SMase) activity. This results in the hydrolysis of sphingomyelin (SM) into ceramide, which is implicated in various cellular functions. Although ceramide regulates phospholipase D (PLD) activity, there is controversy about this relationship. Thus we investigated whether the effect of bradykinin (BK), a proinflammatory factor and vasodilator, was mediated by ceramide signal transduction and by PLD. In rabbit cortical collecting duct (RCCD) cells, BK increased SM levels and decreased ceramide levels in a time-dependent manner. Thus SMase activity was inhibited by BK. Also, the production of ceramide was regulated in a concentration-dependent manner. The BK-B1 antagonist [Lys-des-Arg9,Leu8]BK did not affect ceramide signal transduction but the BK-B2 antagonist (Hoe-140) blocked the effect of BK on SMase, suggesting that the BK-B2 receptor mediates BK-induced inhibition of ceramide generation. Our results show that exogenous SMase significantly hydrolyzed endogenous SM to form ceramide and weakly activated PLD. In contrast, BK induced a significant activation of PLD. However, additive effects of BK and ceramide on PLD activity were not observed. We concluded that in RCCD cells, the BK-induced second messengers ceramide and phosphatidic acid were generated by distinct signal transduction mechanisms, namely the SMase and PLD pathways.
Liu
G
G
Departments of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5.
Kleine
L
L
Nasrallah
R
R
Hébert
R L
RL
D000818:Animals; D001920:Bradykinin / Q000494:pharmacology*; D002518:Ceramides / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D004347:Drug Interactions; D004789:Enzyme Activation / Q000502:physiology; D007672:Kidney Cortex; D007685:Kidney Tubules, Collecting / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D009994:Osmolar Concentration; D010739:Phospholipase D / Q000378:metabolism*; D011817:Rabbits; D018002:Receptors, Bradykinin / Q000502:physiology; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism / Q000494:pharmacology; D013109:Sphingomyelins / Q000378:metabolism; D013997:Time Factors
D002518:Ceramides; D018002:Receptors, Bradykinin; D013109:Sphingomyelins; D013108:Sphingomyelin Phosphodiesterase; D010739:Phospholipase D; D001920:Bradykinin