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 A 2 (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 A 2 (TxA2)-synthase inhibitor; and SQ29548, a TxA 2-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. renal vasoconstriction; angiotensin II; sphingomyelinase; phospholipase A2; cyclooxygenase; thromboxane A2 SPHINGOLIPIDS ARE A FAMILY of lipids that play essential roles as structural cell membrane components and also serve as substrates for enzymes that generate second messengers involved in cell signaling. Thus sphingolipids can be hydrolyzed by sphingomyelinases (SMases) (43). SMases are divided into three major classes, alkaline, acid, and neutral, according to the optimal pH for their activity, primary structure, and localization (15). Acid and alkaline SMases contribute to the hydrolysis of sphingomyelin in the luminal border of cells, in the extracellular space, or in the endosomal system, whereas neutral SMase (nSMase) functions in the inner leaflet of the plasma membrane (32). SMases cleave the phosphodiester linkage of sphingomyelin to produce phosphocholine and ceramide.

Prostaglandins in the pathogenesis of kidney diseases

“…One previous study reported that increased level of vascular ceramide induced by AngII contributed to the pathogenesis of renal injury possibly through TXA2-mediated vasoconstriction [ 144 , 145 ]. Another study was also in line with this conclusion, showing that AngII/AT1 receptor/nSMase/ceramide-PLA2/TXA2 pathway contributed to the regulation of renal vasoconstriction [ 146 ]. In a model of type 2 diabetes, a TXA2 synthase inhibitor was beneficial in reducing glomerular lesion and proteinuria [ 147 ].…”

Small-hairpin RNA and pharmacological targeting of neutral sphingomyelinase prevent diaphragm weakness in rats with heart failure and reduced ejection fraction

“…Enhanced angiotensin II signaling in carotid body chemoreceptors contributes to hyperpnea in HFREF (52). GW4869 prevents vasoconstriction induced by angiotensin II in rat kidneys (6). Thus, GW4869 may have inhibited angiotensin II signaling in carotid body chemoreceptors.…”

Plasma lipidomic biomarker analysis reveals distinct lipid changes in vascular dementia

“…However, all VaD patients showed a higher trend of Cer under the influence of these 2 risk factors. This is important since increased Cer can contribute to vasoconstriction and ischaemic injury through increased levels of TXA2 release in the vasculature [52] . Increased Cer can also impair the activity of glycogen synthase 3 activity which may lead to some of the physiological changes observed in type 2 diabetes and VaD [53] .…”