A novel lipid natriuretic factor in the renal medulla: sphingosine-1-phosphate

Abstract

Zhu Q, Xia M, Wang Z, Li P, Li N. A novel lipid natriuretic factor in the renal medulla: sphingosine-1-phosphate. Am J Physiol Renal Physiol 301: F35-F41, 2011. First published April 6, 2011 doi:10.1152/ajprenal.00014.2011.-Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite formed by phosphorylation of sphingosine. S1P has been indicated to play a significant role in the cardiovascular system. It has been shown that the enzymes for S1P metabolism are expressed in the kidneys. The present study characterized the expression of S1P receptors in the kidneys and determined the role of S1P in the control of renal hemodynamics and sodium excretion. Real-time RT-PCR analyses showed that S1P receptors S1P1, S1P2, and S1P3 were most abundantly expressed in the renal medulla. Immunohistochemistry revealed that all three types of S1P receptors were mainly located in collecting ducts. Intramedullary infusion of FTY720, an S1P agonist, produced a dramatic increase in sodium excretion by twofold and a small but significant increase in medullary blood flow (16%). Administration of W146, an S1P1 antagonist, into the renal medulla blocked the effect of FTY720 and decreased the sodium excretion by 37% when infused alone. The antagonists of S1P2 and S1P3 had no effect. FTY720 produced additive natriuretic effects in combination with different sodium transporter inhibitors except amiloride, an epithelial sodium channel blocker. In the presence of nitric oxide synthase inhibitor L-NAME, FTY720 still increased sodium excretion. These data suggest that S1P produces natriuretic effects via activation of S1P1 in the renal medulla and this natriuretic effect may be through inhibition of epithelial sodium channel, which is nitric oxide independent. It is concluded that S1P is a novel diuretic factor in the renal medulla and may be an important regulator of sodium homeostasis. renal blood flow; sodium transporter; nitric oxide; collecting duct SPHINGOLIPIDS WERE ORIGINALLY thought to serve only as structural components of mammalian cell membranes. In recent years, sphingolipid metabolites are emerging as important lipid signaling molecules. Among them, sphingosine-1-phosphate (S1P) is known to play important roles in cellular processes in various organ systems including cardiovascular system and kidney (15,29). S1P is formed by phosphorylation of sphingosine catalyzed by sphingosine kinase and acts via its G protein-coupled receptors (17,29). Five members of S1P receptor family have been identified and termed S1P1-S1P5 (17, 29). The S1P1, S1P2, and S1P3 are ubiquitously expressed, while S1P4 is predominantly expressed in the lung and lymphoid system, and S1P5 is mainly in brain tissue (17,29). The expression and activity of sphingosine kinase have been detected in the kidneys (1, 10) and the mRNAs of S1P receptors are also present in the kidneys (17). It has been shown that S1P protects the kidneys from ischemic injury (2,27). It has also been demonstrated that S1P regulates vascular functions (14, 23). Therefore, it is p...

Sphingosine-1-Phosphate Evokes Unique Segment-Specific Vasoconstriction of the Renal Microvasculature

“…detected in whole kidney tissue, renal medulla, and glomeruli 11,12 ; however, the distribution of S1P receptor expression in the renal microvasculature has not been studied. We demonstrate here that both S1P1 and S1P2 proteins are abundantly present in isolated preglomerular microvessels, whereas S1P3, S1P4, and S1P5 receptor protein expression was not detected.…”

“…In addition, the lack of detection of S1P4 receptors in renal microvessels agrees with the findings of Ota et al, who reported positive staining for S1P4 receptor protein in pulmonary arteries but not intrarenal arteries. 39 Furthermore, to distinguish between endothelial or tubular cell expression, 11,12 we isolated MVSMCs from preglomerular microvessels. Consistent with Western blot data, S1P1 and S1P2, but not S1P3, receptors were strongly detected in isolated MVSMCs.…”

“…[3][4][5] Studies in animals show that application of exogenous S1P causes either vasoconstriction or vasodilation of isolated arteries from several vascular beds. 3,4 Although S1P receptor expression is detected in kidneys, [11][12][13] little is known about the effects of S1P on renal microvascular function. Early studies showed that S1P evoked vasoconstriction in isolated intrarenal arteries.…”

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

“…Recently, the expression of SphK1 as well as S1PRs was demonstrated in whole kidney and in isolated renal cells. In the rat, S1P1-3 are more abundant in the medullary than in the cortical CD [189] . The cellular localization (i.e., apical or basolateral) remains uncertain to date.…”

“…This suggests that thenatriuretic and diuretic effects of S1P1 stem from PC. Finally it can also be noted that a S1P1 antagonist has anti-natriuretic properties [189] . The main characteristics of glomerulonephritis (proliferation of mesangial cells, stimulation of matrix production and inflammation) may involved the SphK1/ S1P signaling system.…”