Inhibition of Sphingosine 1-Phosphate Receptor 2 Protects against Renal Ischemia-Reperfusion Injury

Abstract

Activation of the sphingosine 1-phosphate receptor 1 (S1P 1 R) protects against renal ischemia-reperfusion (IR) injury and inflammation, but the role of other members of this receptor family in modulating renal IR injury is unknown. We found that a selective S1P 2 R antagonist protected against renal IR injury in a dosedependent manner. Consistent with this observation, both S1P 2 R-deficient mice and wild-type mice treated with S1P 2 R small interfering RNA had reduced renal injury after IR. In contrast, a selective S1P 2 R agonist exacerbated renal IR injury. The S1P 2 R antagonist increased sphingosine kinase-1 (SK1) expression via Rho kinase signaling in renal proximal tubules; the S1P 2 R agonist decreased SK1. S1P 2 R antagonism failed to protect the kidneys of SK1-deficient mice or wild-type mice pretreated with an SK1 inhibitor or an S1P 1 R antagonist, suggesting that the renoprotection conferred by S1P 2 R antagonism results from pathways involving activation of S1P 1 R by SK1. In cultured human proximal tubule (HK-2) cells, the S1P 2 R antagonist selectively upregulated SK1 and attenuated both H 2 O 2 -induced necrosis and TNF-a/cycloheximideinduced apoptosis; the S1P 2 R agonist had the opposite effects. In addition, increased nuclear hypoxia inducible factor-1a was critical in mediating the renoprotective effects of S1P 2 R inhibition. Finally, induction of SK1 and S1P 2 R in response to renal IR and S1P 2 R antagonism occurred selectively in renal proximal tubule cells but not in renal endothelial cells. Taken together, these data suggest that S1P 2 R may be a therapeutic target to attenuate the effects of renal IR injury. AKI is a major clinical complication with high mortality, morbidity, and cost. 1,2 Renal ischemia and reperfusion (IR) injury is a major cause of perioperative AKI for patients undergoing surgery involving the kidney, liver, or aorta. 3,4 Unfortunately, the severity and incidence of AKI have been increasing, without any improvements in therapy or patient survival over the past 50 years. 5 The incidence of renal dysfunction in high-risk patients after major cardiovascular, hepatobiliary, or aortic surgery approaches 70%-80%. 3,4,6 Despite continued research searching for renal protective agents, there are no proven therapies to reduce AKI in the perioperative setting 1,7 Sphingolipids are pleiotropic regulators of kidney physiology that modulate diverse pathways of cell death, including necrosis, apoptosis, inflammation, and immunity. 8,9 In particular, phosphorylation of sphingosine by sphingosine kinases (SK1 and SK2) leads to the formation of sphingosine 1-phosphate (S1P), a lysophospholipid targeting G-protein-coupled receptor that has diverse extracellular as well as intracellular effects. 9 Of five G-protein-coupled receptors for S1P, activation of endothelial S1P 1 R receptor (S1P 1 R) reduces permeability and maintains the integrity of the vascular endothelial cell

Sphingosine 1-Phosphate in Renal Diseases

“…Besides this protective effect of macrophage S1P 3 , the authors also showed that the S1P 1 mediates a renal protection against IRI that is independent of macrophages which is in line with several previous studies [48,82]. Furthermore, it was shown that the S1P 2 agonist SID46371153 exacerbated renal IRI, whereas the S1P 2 antagonist JTE-013 protected against renal IRI [50]. In terms of mechanism, these authors showed that inhibition of S1P 2 led to Rho kinase and HIF-1α activation, SK-1 up-regulation, S1P generation and activation of S1P 1 that consequently triggered renoprotection.…”

“…Additionally, overexpression of SK-1 in HK-2 cells also protected against peroxide-induced necrosis and led to enhanced heat shock protein 27 expression that was reversed by S1P 1 antagonism [49]. Finally, Park et al [50] showed that the selective S1P 2 antagonist JTE-013 induced SK-1 expression and further attenuated necrosis and apoptosis in HK-2 cells, whereas a S1P 2 agonist had the opposite effect. Indeed, the finding that a receptor antagonist in the absence of the receptor ligand has gene inducing capability is surprising at a first glance and it can presently not be excluded that JTE-013 may have additional cellular effects, e.g.…”

Modulatory Effects of Fingolimod (FTY720) on the Expression of Sphingolipid Metabolism-Related Genes in an Animal Model of Alzheimer’s Disease

“…These pathways relay their signals, e.g., to transcription factors such as the activator protein AP-1, or nuclear factor κB (NF-κB). Some relevant examples of S1PR influence on gene regulation include the feedback impact of S1PR2 activation on SphK1 expression, or induction of the cyclooxygenase COX-2 by S1PR3 (which can lead to free radical buildup)-both occur via AP-1 [33][34][35]. Importantly, CERS4 and CERS5 genes are also regulated by AP-1 [36].…”

New insights into sodium transport regulation in the distal nephron: Role of G-protein coupled receptors

“…The main characteristics of glomerulonephritis (proliferation of mesangial cells, stimulation of matrix production and inflammation) may involved the SphK1/ S1P signaling system. Indeed, many studies have shown that S1P1, S1P2, and S1P3 are involved in inflammation and fibrosis in the glomerulus and proximal tubule [191][192][193] . However, so far, investigation of the specific pathophysiological contribution of each S1P receptor and SphK subtypes are not sufficiently selective and potent to yield clear-cut answers as to which of these should be targeted for treatment [194] .…”