title: Involvement of neutral sphingomyelinase in the angiotensin II signaling pathway.
abstract: The possibility that angiotensin II (ANG II) exerts its effects through the activation of neutral sphingomyelinase (nSMase) has not been tested in kidneys. The results of the present study provide evidence for the activity and expression of nSMase in rat kidneys. In isolated perfused rat kidney, ANG II-induced renal vasoconstriction was inhibited by GW4869, an inhibitor of nSMase. We used nSMase for investigating the signal transduction downstream of ceramide. nSMase constricted the renal vasculature. An inhibitor of ceramidase (CDase), N-oleoylethanolamine (OEA), enhanced either ANG II- or nSMase-induced renal vasoconstriction. To demonstrate the interaction between the nSMase and cytosolic phospholipase A2 (cPLA2) signal transduction pathways, we evaluated the response to nSMase in the presence and absence of inhibitors of arachidonic acid (AA) metabolism: arachidonyl trifluoromethyl ketone (AACOCF3), an inhibitor of cPLA2; 5,8,11,14-eicosatetraynoic acid (ETYA), an inhibitor of all AA pathways; indomethacin, an inhibitor of cyclooxygenase (COX); furegrelate, a thromboxane A2 (TxA2)-synthase inhibitor; and SQ29548, a TxA2-receptor antagonist. In these experiments, the nSMase-induced renal vasoconstriction decreased. ANG II or nSMase was associated with an increase in the release of thromboxane B2 (TxB2) in the renal perfusate of isolated perfused rat kidney. In addition, the coexpression of the ceramide with cPLA2, was found in the smooth muscle layer of intrarenal vessels. Our results suggest that ANG II stimulates ceramide formation via the activation of nSMase; thus ceramide may indirectly regulate vasoactive processes that modulate the activity of cPLA2 and the release of TxA2.
authors.affiliation: Department of Molecular Biology, Instituto Nacional de Cardiología I. Ch., Mexico City, Mexico; Department of Nephrology, Instituto Nacional de Cardiología I. Ch., Mexico City, Mexico; maria.bautista@cardiologia.org.mx rociobtst@yahoo.com.
authors.forename: Rocio
authors.initials: R
authors.lastname: Bautista-Pérez
authors.affiliation: Department of Pharmacology, Instituto Nacional de Cardiología I. Ch., Mexico City, Mexico;
authors.forename: Leonardo
authors.initials: L
authors.lastname: del Valle-Mondragón
authors.affiliation: Department of Physiology, Instituto Nacional de Cardiología I. Ch., Mexico City, Mexico; and.
authors.forename: Agustina
authors.initials: A
authors.lastname: Cano-Martínez
authors.affiliation: Department of Molecular Biology, Instituto Nacional de Cardiología I. Ch., Mexico City, Mexico;
authors.forename: Oscar
authors.initials: O
authors.lastname: Pérez-Méndez
authors.affiliation: CINVESTAV-Monterrey. Mexico City, Mexico.
authors.forename: Bruno
authors.initials: B
authors.lastname: Escalante
authors.affiliation: Department of Nephrology, Instituto Nacional de Cardiología I. Ch., Mexico City, Mexico;
authors.forename: Martha
authors.initials: M
authors.lastname: Franco
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology / Q000502:physiology*; D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D001597:Benzylidene Compounds / Q000494:pharmacology; D002518:Ceramides / Q000502:physiology; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000494:pharmacology / Q000502:physiology*; D007668:Kidney / Q000098:blood supply / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D054467:Phospholipases A2 / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology*; D013929:Thromboxane B2 / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D000814:Aniline Compounds; D001597:Benzylidene Compounds; D002518:Ceramides; C468773:GW 4869; D047908:Intracellular Signaling Peptides and Proteins; C491113:Nsmaf protein, rat; D000804:Angiotensin II; D013929:Thromboxane B2; D054467:Phospholipases A2
keywords: angiotensin II; cyclooxygenase; phospholipase A2; renal vasoconstriction; sphingomyelinase; thromboxane A2