sphingosine-1-phosphate and Kidney-Diseases

In the past few decades, sphingolipids and sphingolipid metabolites have gained attention because of their essential role in the pathogenesis and progression of kidney diseases. Studies in models of experimental and clinical nephropathies have described accumulation of sphingolipids and sphingolipid metabolites, and it has become clear that the intracellular sphingolipid composition of renal cells is an important determinant of renal function. Proper function of the glomerular filtration barrier depends heavily on the integrity of lipid rafts, which include sphingolipids as key components. In addition to contributing to the structural integrity of membranes, sphingolipid metabolites, such as sphingosine-1-phosphate (S1P), play important roles as second messengers regulating biologic processes, such as cell growth, differentiation, migration, and apoptosis. This review will focus on the role of S1P in renal cells and how aberrant extracellular and intracellular S1P signaling contributes to the pathogenesis and progression of kidney diseases.

Topics: Animals; Apoptosis; Cell Cycle; Cell Differentiation; Cell Movement; Gene Expression Regulation; Glomerular Filtration Rate; Humans; Kidney; Kidney Diseases; Kidney Transplantation; Lysophospholipids; Membrane Microdomains; Mice; Second Messenger Systems; Signal Transduction; Sphingolipids; Sphingosine

Because of its highly bioactive properties sphingosine 1-phosphate (S1P) is an attractive target for the treatment of several diseases. Since the expression of sphingosine kinases as well as S1P receptors was demonstrated in the kidney, questions about the physiological and pathophysiological functions of S1P in this organ have been raised. In this review, we summarize the current state of knowledge about S1P-mediated functions in the kidney. A special focus is put on S1P modulated signal transduction in renal glomerular and tubular cells and consequences for the development and treatment of several kidney diseases, diabetic nephropathy, glomerulonephritis, ischemia-reperfusion injury, as well as for Wilms tumor progression.

Topics: Animals; Disease Models, Animal; Humans; Kidney Diseases; Kidney Glomerulus; Kidney Tubules; Lysophospholipids; Phosphotransferases (Alcohol Group Acceptor); Receptors, Lysosphingolipid; Sphingosine

The major sphingolipid metabolite, sphingosine-1-phosphate (S1P), has important biological functions. S1P is the ligand for a family of five G-protein-coupled receptors with distinct signaling pathways that regulate angiogenesis, vascular maturation, immunity, chemotaxis, and other important biological pathways. Recently, clinical trials have targeted S1P receptors (S1PRs) for autoimmune diseases and transplantation and have generated considerable interest in developing additional, more selective compounds. This review summarizes current knowledge on the biology of S1P and S1PRs that forms the basis for future drug development and the treatment of kidney disease.

Topics: Animals; Cell Survival; Drug Design; Humans; Kidney Diseases; Lysophospholipids; Mice; Receptors, Lysosphingolipid; Sphingosine

Alterations in the metabolism of sphingolipids, a class of biologically active molecules in cell membranes with direct effect on vascular homeostasis, are increasingly recognized as important determinant in different vascular disorders. However, it is not clear whether sphingolipids are implicated in the pathogenesis of hypertension-related cerebrovascular and renal damage. In this study, we evaluated the existence of possible abnormalities related to the sphingolipid metabolism in the brain and kidneys of two well validated spontaneously hypertensive rat strains, the stroke-prone (SHRSP) and the stroke-resistant (SHRSR) models, as compared to the normotensive Wistar Kyoto (WKY) rat strain. Our results showed a global alteration in the metabolism of sphingolipids in both cerebral and renal tissues of both hypertensive strains as compared to the normotensive rat. However, few defects, such as reduced expression of enzymes involved in the metabolism/catabolism of sphingosine-1-phosphate and in the de novo biosynthetic pathways, were exclusively detected in the SHRSP. Although further studies are necessary to fully understand the significance of these findings, they suggest that defects in specific lipid molecules and/or their related metabolic pathways may likely contribute to the pathogenesis of hypertensive target organ damage and may eventually serve as future therapeutic targets to reduce the vascular consequences of hypertension.

Topics: Animals; Brain; Brain Injuries; Hypertension; Kidney; Kidney Diseases; Lysophospholipids; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sphingosine

Topics: Aged; Biomarkers; Calcimimetic Agents; Chromatography, High Pressure Liquid; Cinacalcet; Down-Regulation; Female; Humans; Hyperparathyroidism, Secondary; Kidney Diseases; Lysophospholipids; Male; Middle Aged; Naphthalenes; Renal Dialysis; Sphingosine; Treatment Outcome

Sphingosine-1-phosphate (S1P), produced by sphingosine kinase 1 (SphK1) or kinase 2 (SphK2), mediates biological effects through intracellular and/or extracellular mechanisms. Here we determined a role for these kinases in kidney injury of wild-type mice following ischemia-reperfusion. SphK1 but not SphK2 mRNA expression and activity increased in the kidney following injury relative to sham-operated animals. Although SphK1(-/-) mice had no alteration in renal function following injury, mice with a disrupted SphK2 gene (SphK2(tr/tr)) had histological damage and impaired function. The immune-modulating pro-drug, FTY720, an S1P agonist failed to provide protection in SphK2(tr/tr) mice. Injured kidneys of these mice showed increased neutrophil infiltration and neutrophil chemokine expression along with a 3- to 5-fold increase in expression of the G-protein-coupled receptor S1P(3) compared to heterozygous SphK2(+/tr) mice. Kidney function and reduced vascular permeability were preserved in S1P(3)(-/-) compared to S1P(3)(+/-) mice after ischemia-reperfusion injury, suggesting increased S1P(3) mRNA may play a role in the injury of SphK2(tr/tr) mice. Our study suggests that constitutive expression of SphK2 may contribute to reduced ischemia-reperfusion injury of the kidney, and its absence may enhance injury due to increased neutrophil infiltration and S1P(3) activation. We also confirm that SphK2 is necessary to mediate the protective effects of FTY720.

Topics: Animals; Fingolimod Hydrochloride; Gene Expression Regulation, Enzymologic; Kidney; Kidney Diseases; Lysophospholipids; Mice; Mice, Knockout; Phosphotransferases (Alcohol Group Acceptor); Propylene Glycols; Reperfusion Injury; RNA, Messenger; Sphingosine

Renal fibrosis contributes to glomerulosclerosis and tubulointerstitial damage in chronic kidney disease. A well-established pathway implicated in the progression of fibrosis is the induction of connective tissue growth factor by transforming growth factor-beta, resulting in the accumulation of extracellular matrix proteins. Ren and colleagues demonstrate that sphingosine kinase-1 is involved in the regulation of this pathway in the glomerulus. This raises the possibility of targeting sphingosine kinase-1 to prevent fibrosis in chronic kidney disease patients.

Topics: Animals; Chronic Disease; Connective Tissue Growth Factor; Disease Progression; Fibrosis; Humans; Kidney Diseases; Lysophospholipids; Phosphotransferases (Alcohol Group Acceptor); Podocytes; Protein Kinase Inhibitors; Sphingosine; Transforming Growth Factor beta2

The inhalational anesthetic isoflurane has been shown to protect against renal ischemia-reperfusion (IR) injury. Previous studies demonstrated that isoflurane modulates sphingolipid metabolism in renal proximal tubule cells. We sought to determine whether isoflurane stimulates sphingosine kinase (SK) activity and synthesis of sphingosine-1-phosphate (S1P) in renal proximal tubule cells to mediate renal protection via the S1P signaling pathway. Isoflurane anesthesia reduced the degree of renal failure and necrosis in a murine model of renal IR injury. This protection with isoflurane was reversed by SK inhibitors (DMS and SKI-II) as well as an S1P(1) receptor antagonist (VPC23019). In addition, mice deficient in SK1 enzyme were not protected from IR injury with isoflurane. SK activity as well as SK1 mRNA expression increased in both cultured human proximal tubule cells (HK-2) and mouse kidneys after exposure to isoflurane. Finally, isoflurane increased the generation of S1P in HK-2 cells. Taken together, our findings indicate that isoflurane activates SK in renal tubule cells and initiates S1P-->S1P(1) receptor signaling to mediate the renal protective effects. Our findings may help to unravel the cellular signaling pathways of volatile anesthetic-mediated renal protection and lead to new therapeutic applications of inhalational anesthetics during the perioperative period.

Topics: Anesthetics, Inhalation; Animals; Cell Line; Creatinine; Enzyme Inhibitors; Humans; Isoflurane; Kidney Diseases; Kidney Tubules; Lysophospholipids; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Necrosis; Phosphotransferases (Alcohol Group Acceptor); Receptors, Lysosphingolipid; Reperfusion Injury; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Sphingosine

Our prior in vitro studies indicate that sphingosine 1-phosphate (S1P), a phospholipid angiogenic factor, produces endothelial cell barrier enhancement through ligation of endothelial differentiation gene family receptors. We hypothesized that S1P may reduce the vascular leak associated with acute lung injury and found that S1P infusion produced a rapid and significant reduction in lung weight gain (more than 50%) in the isolated perfused murine lung. The effect of S1P was next assessed in a murine model of LPS-mediated microvascular permeability and inflammation with marked increases in parameters of lung injury at both 6 and 24 hours after intratracheal LPS. Each parameter assessed was significantly reduced by intravenous S1P (1 microM final) and in selected experiments by the S1P analogue FTY720 (0.1 mg/kg, intraperitoneally) delivered 1 hour after LPS. S1P produced an approximately 40-50% reduction in LPS-mediated extravasation of Evans blue dye albumin, bronchoalveolar lavage protein content, and lung tissue myeloperoxidase activity (reflecting phagocyte infiltration). Consistent with systemic barrier enhancement, S1P significantly decreased Evans blue dye albumin extravasation and myeloperoxidase content in renal tissues of LPS-treated mice. These studies indicate that S1P significantly decreases pulmonary/renal vascular leakage and inflammation in a murine model of LPS-mediated acute lung injury and may represent a novel therapeutic strategy for vascular barrier dysfunction.

Topics: Animals; Bronchoalveolar Lavage Fluid; Capillary Permeability; Disease Models, Animal; Endothelial Cells; Endotoxins; Fingolimod Hydrochloride; Immunosuppressive Agents; Kidney; Kidney Diseases; Lipopolysaccharides; Lung; Lysophospholipids; Male; Mice; Mice, Inbred C57BL; Neutrophils; Organ Size; Perfusion; Peroxidase; Pneumonia; Propylene Glycols; Respiratory Distress Syndrome; Sphingosine; Time Factors