sphingosine-kinase and Albuminuria

The sphingosine 1-phosphate (S1P) is a bioactive sphingolipid that is now appreciated as key regulatory factor for various cellular functions in the kidney, including matrix remodeling. It is generated by two sphingosine kinases (Sphk), Sphk1 and Sphk2, which are ubiquitously expressed, but have distinct enzymatic activities and subcellular localizations. In this study, we have investigated the role of Sphk2 in podocyte function and its contribution to diabetic nephropathy. We show that streptozotocin (STZ)-induced nephropathy and albuminuria in mice is prevented by genetic depletion of Sphk2. This protection correlated with an increased protein expression of the transcription factor Wilm's tumor suppressor gene 1 (WT1) and its target gene nephrin, and a reduced macrophage infiltration in immunohistochemical renal sections of STZ-treated Sphk2

Topics: Albuminuria; Animals; Diabetic Nephropathies; Genes, Tumor Suppressor; Membrane Proteins; Mice; Mice, Knockout; Phosphotransferases (Alcohol Group Acceptor); Podocytes; Streptozocin; WT1 Proteins

FTY720, a new immunomodulatory drug with low cytotoxicity, is currently used to treat multiple sclerosis. In this study, we investigated the effects of FTY720 on inflammatory cell infiltration in albumin overload-induced nephropathy of rats.. Male Wistar rats were subjected to right-side nephrectomy and divided into 3 groups. One week after the surgery, albumin overload (AO) group was treated with BSA (5 g·kg(-1)·d(-1), ip) for 9 weeks; AO+FTY720 group was given BSA (5 g·kg(-1)·d(-1), ip) plus FTY720 (0.5 g·kg(-1)·d(-1), ip) for 9 weeks; and control group received daily ip injection of equivalent volume of saline. All rats were killed 9 weeks after nephrectomy.. AO rats exhibited gradually increased urinary protein excretion accompanied by elevated urinary N-acetyl-β-O-glucosaminidase activity, and both reached their peak values at week 7. Furthermore, AO significantly increased lymphocytes and monocytes in circulation and the inflammatory cells recruited to tubulointerstitium, and the expression of inflammatory cytokines MCP-1, TNF-α and IL-6, as well as sphingosine 1-phosphate (S1P) receptors S1pr1 and S1pr3, and S1P-synthesizing enzyme sphingosine kinase 1 (Sphk1) in the kidney. Concomitant administration of FTY720 significantly attenuated all the AO-induced pathological changes.. FTY720 alleviates tubulointerstitium inflammation in an AO rat model of nephropathy via down-regulation of the Sphk1 pathway.

Topics: Acetylglucosaminidase; Albuminuria; Animals; Anti-Inflammatory Agents; Disease Models, Animal; Down-Regulation; Fingolimod Hydrochloride; Immunosuppressive Agents; Inflammation Mediators; Kidney Tubules; Lymphocytes; Lysophospholipids; Macrophages; Male; Nephritis, Interstitial; Phosphotransferases (Alcohol Group Acceptor); Propylene Glycols; Rats, Wistar; Receptors, Lysosphingolipid; Signal Transduction; Sphingosine; Sphingosine-1-Phosphate Receptors; Time Factors

Berberine (BBR) was previously found to have beneficial effects on renal injury in experimental diabetic rats. However, the mechanisms underlying the effects are not fully understood. Sphingosine kinase-Sphingosine 1-phosphate (SphK-S1P) signaling pathway has been implicated in the pathogenesis of diabetic nephropathy (DN). The aim of this study was to investigate the effects of BBR on renal injury and the activation of SphK-S1P signaling pathway in alloxan-induced diabetic mice with nephropathy. Alloxan-induced diabetic mice were treated orally with BBR (300 mg/kg/day) or vehicle for 12 weeks. BBR inhibited the increases in fasting blood glucose, kidney/body weight ratio, blood urea nitrogen, serum creatinine and 24-h albuminuria in diabetic mice. It also prevented renal hypertrophy, TGF-beta1 synthesis, FN and Col IV accumulation. Moreover, BBR down-regulated the elevated staining, activity and levels of mRNA and protein of SphK1, and S1P production as well. These findings suggest that the inhibitory effect of BBR on the activation of SphK-S1P signaling pathway in diabetic mouse kidney is a novel mechanism by which BBR partly exerts renoprotective effects on DN.

Topics: Albuminuria; Animals; Berberine; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Glucose; Kidney; Lysophospholipids; Male; Mice; Mice, Inbred C57BL; Phosphotransferases (Alcohol Group Acceptor); Random Allocation; Signal Transduction; Sphingosine; Transforming Growth Factor beta1

Transforming growth factor-beta2 (TGF-beta2) stimulates the expression of pro-fibrotic connective tissue growth factor (CTGF) during the course of renal disease. Because sphingosine kinase-1 (SK-1) activity is also upregulated by TGF-beta, we studied its effect on CTGF expression and on the development of renal fibrosis. When TGF-beta2 was added to an immortalized human podocyte cell line we found that it activated the promoter of SK-1, resulting in upregulation of its mRNA and protein expression. Further, depletion of SK-1 by small interfering RNA or its pharmacological inhibition led to accelerated CTGF expression in the podocytes. Over-expression of SK-1 reduced CTGF induction, an effect mediated by intracellular sphingosine-1-phosphate. In vivo, SK-1 expression was also increased in the podocytes of kidney sections of patients with diabetic nephropathy when compared to normal sections of kidney obtained from patients with renal cancer. Similarly, in a mouse model of streptozotocin-induced diabetic nephropathy, SK-1 and CTGF were upregulated in podocytes. In SK-1 deficient mice, exacerbation of disease was detected by increased albuminuria and CTGF expression when compared to wild-type mice. Thus, SK-1 activity has a protective role in the fibrotic process and its deletion or inhibition aggravates fibrotic disease.

Topics: Albuminuria; Animals; Cell Line; Connective Tissue Growth Factor; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Down-Regulation; Fibrosis; Gene Expression Regulation, Enzymologic; Humans; Lysophospholipids; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mutation; Phosphotransferases (Alcohol Group Acceptor); Podocytes; Promoter Regions, Genetic; Protein Kinase Inhibitors; RNA Interference; RNA, Messenger; Smad4 Protein; Sphingosine; Time Factors; Transforming Growth Factor beta1; Transforming Growth Factor beta2; Up-Regulation