Annexin A1 modulates macula densa function by inhibiting cyclooxygenase 2

Abstract

Annexin A1 (ANXA1) exerts anti-inflammatory effects through multiple mechanisms including inhibition of prostaglandin synthesis. Once secreted, ANXA1 can bind to G protein-coupled formyl peptide receptors (Fpr) and activate diverse cellular signaling pathways. ANXA1 is known to be expressed in cells of the juxtaglomerular apparatus, but its relation to the expression of cyclooxygenase 2 (COX-2) in thick ascending limb and macula densa cells has not been elucidated. We hypothesized that ANXA1 regulates the biosynthesis of COX-2. ANXA1 abundance in rat kidney macula densa was extensively colocalized with COX-2 (95%). Furosemide, an established stimulus for COX-2 induction, caused enhanced expression of both ANXA1 and COX-2 with maintained colocalization (99%). In ANXA1-deficient mice, COX-2-positive cells were more numerous than in control mice (+107%; normalized to glomerular number; P < 0.05) and renin expression was increased (+566%; normalized to glomerular number; P < 0.05). Cultured macula densa cells transfected with full-length rat ANXA1 revealed downregulation of COX-2 mRNA (-59%; P < 0.05). Similarly, treatment with dexamethasone suppressed COX-2 mRNA in the cells (-49%; P < 0.05), while inducing ANXA1 mRNA (+56%; P < 0.05) and ANXA1 protein secretion. Inhibition of the ANXA-1 receptor Fpr1 with cyclosporin H blunted the effect of dexamethasone on COX-2 expression. These data show that ANXA1 exerts an inhibitory effect on COX-2 expression in the macula densa. ANXA1 may be a novel intrinsic modulator of renal juxtaglomerular regulation by inhibition of PGE(2) synthesis.

Annexin A1 peptide is able to induce an anti-parasitic effect in human placental explants infected by Toxoplasma gondii

“…It is known that COX-2 promotes arachidonic acid breakdown in the plasma membrane, leading to synthesis of prostaglandins and leukotrienes such as prostaglandin E2 [35], justifying our findings. In addition, ANXA1 inhibited COX-2 expression in macula densa through activation of FPR1 in kidney [36].…”

The crosstalk of ABCA1 and ANXA1: a potential mechanism for protection against atherosclerosis

“…ANXA1 also reduces inflammatory responses by inhibiting phospholipase A 2 (PLA 2 ), thereby inhibiting the synthesis of arachidonic acid (AA) and AA-derived metabolites, including thromboxane A2 (TXA 2 ), prostaglandin E 2 (PGE 2 ), PGI 2 , PGD 2 , and PGF2α (Sanches et al 2020 ; Seidel et al 2012 ). ANXA1 also prevents inflammatory responses by reducing nitric oxide synthase (iNOS) and the expression of cyclooxygenase-2 (COX-2), which is a rate-limiting key enzyme of prostaglandin synthesis (Seidel et al 2012 ; Kiani-Esfahani et al 2016 ). ANXA1 also induces macrophage polarization toward a more anti-inflammatory phenotype that secretes IL-10, an anti-inflammatory cytokine (Ferlazzo et al 2003 ; Butcher and Galkina 2015 ; Giannarelli and Wong 2019 ).…”

“…Interestingly, ANXA1 secretion has been shown to require ABCA1 in macrophages and endocrine cells. The ABCA1 inhibitor glyburide blocks ANXA1 secretion (Seidel et al 2012 ). Chapman et al revealed that ABCA1 promotes ANXA1 release in mouse FS and A549 cells.…”

“…ANXA1 binds to and activates the formyl peptide receptor (FPR) on leukocytes and endothelial cells, thereby inhibiting leukocyte migration to inflammatory sites (Senchenkova et al 2019;Parisi et al 2019;Pessolano et al 2019). ANXA1 also reduces inflammatory responses by inhibiting phospholipase A 2 (PLA 2 ), thereby inhibiting the synthesis of arachidonic acid (AA) and AA-derived metabolites, including thromboxane A2 (TXA 2 ), prostaglandin E 2 (PGE 2 ), PGI 2 , PGD 2 , and PGF2α (Sanches et al 2020;Seidel et al 2012). ANXA1 also prevents inflammatory responses by reducing nitric oxide synthase (iNOS) and the expression of cyclooxygenase-2 (COX-2), which is a rate-limiting key enzyme of prostaglandin synthesis (Seidel et al 2012;Kiani-Esfahani et al 2016).…”

Annexin A1 Regulates NLRP3 Inflammasome Activation and Modifies Lipid Release Profile in Isolated Peritoneal Macrophages

“…Therefore, investigations that highlight novel signaling components that regulate inflammasome activation are crucial to prevent or treat human infections/inflammatory diseases. Considering that AnxA1 is a potent anti-inflammatory protein that down-regulates proinflammatory mediator release, phospholipase A 2 and, consequently, the critical cascade pathways of eicosanoid production such as that of cyclooxygenase 2 (COX-2) [17,18], this study evaluated its role in regulating the NLRP3 inflammasome and lipid release by macrophages.…”