sphingosine-1-phosphate and Renal-Insufficiency--Chronic

In 2011, the crystal structure of apolipoprotein M (apoM) and its capacity to bind sphingosine-1-phosphate (S1P) was characterized. Since then, a variety of studies has increased our knowledge on apoM biology and functionality. From being an unknown and hardly significant player in overall metabolism, apoM has gained significant interest.. Key discoveries in the last 2 years have indicated that the apoM/S1P complex has important roles in lipid metabolism (affecting triglyceride turnover), inflammation (a marker of severe sepsis and potentially providing anti-inflammatory signaling) and kidney biology (potential to protect against immunoglobulin A nephropathy).. Several studies suggest a potential for apoM/S1P as biomarkers for inflammation, sepsis and nephropathy. Also, a novel chaperone is characterized and could have potential as a drug for treatment in inflammation and nephropathy.

Topics: Animals; Apolipoproteins M; Humans; Inflammation; Kidney; Lipid Metabolism; Lysophospholipids; Renal Insufficiency, Chronic; Sphingosine

Farnesoid X receptor (FXR) activation reduces renal inflammation, but the underlying mechanisms remain elusive. Neutrophil extracellular traps (NETs) are webs of DNA formed when neutrophils undergo specialized programmed cell death (NETosis). The signaling lipid sphingosine-1-phosphate (S1P) stimulates NETosis via its receptor on neutrophils. Here, we identify FXR as a negative regulator of NETosis via repressing S1P signaling. We determined the effects of the FXR agonist obeticholic acid (OCA) in mouse models of adenosine phosphoribosyltransferase (APRT) deficiency and Alport syndrome, both genetic disorders that cause chronic kidney disease. Renal FXR activity is greatly reduced in both models, and FXR agonism reduces disease severity. Renal NETosis and sphingosine kinase 1 (

Topics: Animals; Biomarkers; Extracellular Traps; Female; Humans; Inflammation; Male; Mice; Nephritis; Renal Insufficiency, Chronic; Sphingosine

Chronic kidney disease (CKD), characterized by sustained inflammation and progressive fibrosis, is highly prevalent and can eventually progress to end-stage kidney disease. However, current treatments to slow CKD progression are limited. Sphingosine 1-phosphate (S1P), a product of sphingolipid catabolism, is a pleiotropic mediator involved in many cellular functions, and drugs targeting S1P signaling have previously been studied particularly for autoimmune diseases. The primary mechanism of most of these drugs is functional antagonism of S1P receptor-1 (S1P1) expressed on lymphocytes and the resultant immunosuppressive effect. Here, we documented the role of local S1P signaling in perivascular cells in the progression of kidney fibrosis using primary kidney perivascular cells and several conditional mouse models. S1P was predominantly produced by sphingosine kinase 2 in kidney perivascular cells and exported via spinster homolog 2 (Spns2). It bound to S1P1 expressed in perivascular cells to enhance production of proinflammatory cytokines/chemokines upon injury, leading to immune cell infiltration and subsequent fibrosis. A small-molecule Spns2 inhibitor blocked S1P transport, resulting in suppression of inflammatory signaling in human and mouse kidney perivascular cells in vitro and amelioration of kidney fibrosis in mice. Our study provides insight into the regulation of inflammation and fibrosis by S1P and demonstrates the potential of Spns2 inhibition as a treatment for CKD and potentially other inflammatory and fibrotic diseases that avoids the adverse events associated with systemic modulation of S1P receptors.

Topics: Animals; Fibrosis; Humans; Inflammation; Kidney; Lysophospholipids; Mice; Renal Insufficiency, Chronic; Sphingosine

Sphingosine-1-phosphate (S1P) is a bioactive metabolite of sphingolipids and produced by sphingosine kinases (SphK1 and SphK2). SphK1/S1P pathway is implicated in the progression of chronic kidney disease. However, the role of SphK1/S1P pathway in renal injury in hypertension has not been reported. This study tested the hypothesis that SphK1/S1P pathway mediates the kidney damage in DOCA-salt hypertensive mice.. Male wild type (WT) C57BL6 and SphK1 knockout (KO) mice were subjected to unilateral nephrectomy, subcutaneous implant containing 50 mg of deoxycorticosterone acetate (DOCA) and 1% NaCl drinking water for 7 weeks. At the end of experiments, blood pressure data, 24 h urine and kidney samples were collected. Renal mRNA levels of SphK1 were measured by real-time RT-PCR. Markers for fibrogenesis and immune cell infiltration in kidneys were detected using Western blot and immunohistochemistray analysis, respectively. The glomerular morphological changes were examined in kidney tissue slides stained with Periodic-Acid Schiff. Four groups were studied: wild type control (WT-C), WT-DOCA, KO-C and KO-DOCA.. The renal SphK1 mRNA expression was significantly upregulated in WT-DOCA mice, whereas this upregulation of renal SphK1 mRNA was blocked in KO-DOCA mice. There was no difference in DOCA-salt-induced hypertension between WT and KO mice. The urinary albumin was increased in both DOCA-salt groups. However, the albuminuria was significantly lower in KO-DOCA than in WT-DOCA group. There were increases in glomerulosclerosis indices in both DOCA-salt groups, whereas the increases were also significantly lower in KO-DOCA than in WT-DOCA mice. Renal protein levels of α-smooth muscle actin were upregulated in both DOCA-salt groups, but the increase was significant lower in KO-DOCA than in WT-DOCA group. The increased staining areas of collagen detected by Sirius Red-staining in kidney tissue sections were also attenuated in KO-DOCA compared with WT-DOCA mice. In contrast, the increased infiltration of CD43+ (a T cell marker) or CD68+ (a macrophage marker) cells in DOCA-salt kidneys showed no significant difference between WT-DOCA and KO-DOCA mice.. SphK1/S1P signaling pathway mediates kidney damage in DOCA-salt hypertensive mice independent of blood pressure and immune modulation.

Topics: Actins; Albuminuria; Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Blotting, Western; Collagen; Desoxycorticosterone Acetate; Disease Models, Animal; Fibrosis; Hypertension; Immunohistochemistry; Kidney; Leukosialin; Lysophospholipids; Macrophages; Male; Mice; Mice, Knockout; Mineralocorticoids; Nephrectomy; Phosphotransferases (Alcohol Group Acceptor); Renal Insufficiency, Chronic; RNA, Messenger; Signal Transduction; Sodium Chloride, Dietary; Sphingosine; T-Lymphocytes

Topics: Erythrocytes; Humans; Hypoxia; Lysophospholipids; Renal Insufficiency, Chronic; Sphingosine

Hemodialysis (HD) and peritoneal dialysis (PD) are the primary means of managing end stage renal disease (ESRD). However, these treatment modalities are associated with the onset of coagulation abnormalities. Effective management of coagulation risk among these patients requires the identification of surrogate markers that provide an early indication of the coagulation abnormalities. The role of sphingolipids in the manifestation and prediction of coagulation abnormalities among dialysis patients have never been investigated. Herein, we report the first instance of an in depth investigation into the sphingolipid changes among ESRD patients undergoing HD and PD. The results reveal distinct differences in terms of perturbations to specific sphingolipid biosynthetic pathways that are highly dependent on the treatment modality. Our studies also demonstrated strong correlation between specific sphingolipids and coagulation parameters, such as HexCer(d18:1/26:0) and maximal amplitude (MA), SM(d18:1/24:1) and tissue factor pathway inhibitor, and sphingosine 1-phosphate d18:1 and FX (Spearman ρ of 0.93, 0.89, and -0.89, respectively). Furthermore, our study revealed the potential for using HexCer(d18:1/22:0), HexCer(d18:1/24:0), and HexCer(d18:1/26:0) (r

Topics: Adult; Biomarkers; Blood Coagulation; Blood Coagulation Disorders; Chromatography, High Pressure Liquid; Female; Humans; Kidney Failure, Chronic; Lipid Metabolism; Lysophospholipids; Male; Middle Aged; Peritoneal Dialysis; Renal Dialysis; Renal Insufficiency, Chronic; Sphingolipids; Sphingomyelins; Sphingosine

FTY720, a new chemical substance derived from the ascomycete

Topics: Adult; Angiotensin II; Animals; Cell Adhesion; Enzyme-Linked Immunosorbent Assay; Female; Fingolimod Hydrochloride; Humans; Immunohistochemistry; Interleukin-6; Lysophospholipids; Male; Middle Aged; Podocytes; Radioimmunoassay; Rats; Rats, Wistar; Real-Time Polymerase Chain Reaction; Renal Insufficiency, Chronic; Sphingosine; Tumor Necrosis Factor-alpha; Wound Healing; Young Adult