sphingosine-kinase and Diabetic-Nephropathies

Diabetic nephropathy (DN) is the major cause of end-stage renal disease worldwide and its prevalence continues to increase. Currently, therapies for DN provide only partial renoprotection; hence new targets for therapeutic intervention need to be identified. In this review, we summarized the new target, sphingosine kinase-1/sphingosine 1-phosphate (SphK1/S1P) pathway, explored its potential therapeutic role in the prevention and treatment of DN.. Most relevant articles were mainly identified by searching PubMed in English.. Mainly original articles and critical review articles by major pioneer investigators in this field were selected to be reviewed.. SphK1/S1P pathway can be activated by hyperglycemia, advanced glycation end products, and many pro-inflammatory cytokines, which leads to fibronectin, transforming growth factor-β1 up-regulation and AP-1 activation. And then it could promote glomerular mesangial cells proliferation and extracellular matrix accumulation, mediating the initiation and progression of diabetic renal fibrosis.. SphK1/S1P pathway is closely correlated with the pathogenesis of DN. The results suggest that SphK1/S1P pathway as a new target for clinically improving DN in future is of great prospect.

Topics: Diabetic Nephropathies; Extracellular Matrix; Humans; Lysophospholipids; Phosphotransferases (Alcohol Group Acceptor); Signal Transduction; Sphingosine

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

Hyperglycemia induces all isoforms of transforming growth factor β (TGFβ), which in turn play key roles in inflammation and fibrosis that characterize diabetic nephropathy. Sphingosine 1-phosphate (S1P) is a signaling sphingolipid, derived from sphingosine by the action of sphingosine kinase (SK). S1P mediates many biological processes, which mimic TGFβ signaling. To determine the role of SK1 and S1P in inducing fibrosis and inflammation, and the interaction with TGFβ-1, 2 and 3 signalling in diabetic nephropathy, human proximal tubular cells (HK2 cells) were exposed to normal (5 mmol/L) or high (30 mmol/L) glucose or TGFβ-1, -2, -3 ± an SK inhibitor (SKI-II) or SK1 siRNA. Control and diabetic wild type (WT) and SK1(-/-) mice were studied. Fibrotic and inflammatory markers, and relevant downstream signalling pathways were assessed. SK1 mRNA and protein expression was increased in HK2 cells exposed to high glucose or TGFβ1,-2,-3. All TGFβ isoforms induced fibronectin, collagen IV and macrophage chemoattractant protein 1 (MCP1), which were reversed by both SKI-II and SK1 siRNA. Exposure to S1P increased phospho-p44/42 expression, AP-1 binding and NFkB phosphorylation. WT diabetic mice exhibited increased renal cortical S1P, fibronectin, collagen IV and MCP1 mRNA and protein expression compared to SK1(-/-) diabetic mice. In summary, this study demonstrates that inhibiting the formation of S1P reduces tubulointerstitial renal inflammation and fibrosis in diabetic nephropathy.

Topics: Animals; Biomarkers; Cell Line; Diabetic Nephropathies; Dose-Response Relationship, Drug; Enzyme Inhibitors; Extracellular Matrix; Extracellular Signal-Regulated MAP Kinases; Fibrosis; Gene Expression Regulation, Enzymologic; Gene Silencing; Glucose; Humans; Inflammation; Kidney Cortex; Kidney Tubules; Lysophospholipids; Male; Mice; NF-kappa B; Phosphoproteins; Phosphotransferases (Alcohol Group Acceptor); Sphingosine; Transcription Factor AP-1; Transforming Growth Factor beta

Rehmanniae Radix (RR) and Cornus officinalis (CO) are two traditional Chinese medicines widely used in China for treating diabetes mellitus and its complications, such as diabetic nephropathy. Iridoid glycoside of Cornus officinalis (IGCO), triterpenoid acid of Cornus officinalis (TACO) and iridoid glycoside of Rehmanniae Radix (IGRR) formed an innovative formula named combinatorial bioactive parts (CBP). The aims of the present study were to investigate the renoprotective effects of CBP on DN through the inhibition of AGEs/RAGE/SphK1 signaling pathway activation, and identify the advantage of CBP compared with IGCO, TACO, IGRR.. The db/db diabetic renal injury model was used to examine the renoprotective effects of CBP, IGCO, TACO and IGRR. For mechanistic studies, diabetic symptoms, renal functions, and pathohistology of pancreas and kidney were evaluated. AGEs/RAGE/SphK1 pathway were determined.. CBP, IGCO, TACO and IGRR inhibited the decrease in serum insulin levels and the increases in urine volume, food consumption, water intake, TC, TG, glycated serum protein, fasting blood glucose levels, 24h urine protein levels, and serum levels of urea nitrogen and creatinine. It also prevented ECM accumulation and improved the histology of pancreas and kidney, and alleviated the structural alterations in mesangial cells and podocytes in renal cortex. Moreover, CBP, IGCO, TACO and IGRR down-regulated the elevated staining, protein levels of RAGE, SphK1, TGF-β and NF-κB. Among the treatment groups, CBP produced the strongest effects.. These findings suggest that the inhibitory effect of CBP, IGCO, TACO and IGRR on the activation of AGEs/RAGE/SphK1 signaling pathway in db/db diabetic mice kidney is a novel mechanism by which CBP, IGCO, TACO and IGRR exerts renoprotective effects on DN. Among all the groups, CBP produced the strongest effect while IGCO, TACO and IGRR produced weaker effects.

Topics: Animals; Cornus; Diabetes Mellitus; Diabetic Nephropathies; Drug Synergism; Glycation End Products, Advanced; Mice; Mice, Inbred C57BL; NF-kappa B; Phosphotransferases (Alcohol Group Acceptor); Phytotherapy; Plant Extracts; Plant Roots; Receptor for Advanced Glycation End Products; Rehmannia

To investigate the effects of high glucose and the specific antagonist JTE-013 of sphingosine-1-phosphate receptor 2 (S1PR2) on the expressions of sphingosine kinase 1 (Sphk1), S1PR2 and monocyte chemoattractant protein-1 (MCP-1) in rat glomerular mesangial cells.. The cultured rat GMCs were divided into four groups: normal glucose control group (NG, with 5.5 mmol/L glucose), mannitol group (HM, with 5.5 mmol/L glucose and 24.5 mmol/L mannitol), high glucose group (HG, with 30 mmol/L glucose), JTE-013 group (HJ, with 30 mmol/L glucose and 10 μmol/L JTE-013). The mRNA levels of SphK1, S1PR2 and MCP-1 were determined with real-time quantitative PCR in the cells at 0, 12, 24 and 48 hours, respectively, and the protein expression of MCP-1 in the supernatant was determined with ELISA .. Compared with those in normal glucose, the mRNAs of SphK1 and S1PR2 in rat GMCs under high glucose were down-regulated at 12 hours and were then up-regulated as time went on, and peaked at 48 hours. High glucose significantly enhanced the mRNA expression of MCP-1 at 12 hours, and the expression reached the highest levels at 24 hours, but decreased at 48 hours. The protein expression of MCP-1 in rat GMCs time-dependently increased under high glucose compared with that in NG. After GMCs were treated with 10 μmol/L JTE-013 before exposed to high glucose for 24 hours, the mRNA levels of SphK1, S1PR2 and MCP-1 and the protein expression of MCP-1 significantly decreased compared with those in HG.. Inhibition of S1PR2 activity could down-regulate the expressions of SphK1 and MCP-1 in rat GMCs under high glucose.

Topics: Animals; Chemokine CCL2; Diabetic Nephropathies; Down-Regulation; Glucose; Humans; Mesangial Cells; Phosphotransferases (Alcohol Group Acceptor); Rats; Receptors, Lysosphingolipid; Sphingosine-1-Phosphate Receptors

Our previous studies have confirmed that the sphingosine kinase 1 (SphK1)-sphingosine 1-phosphate (S1P) signaling pathway in the kidney under diabetic conditions is closely correlated with the pathogenesis of diabetic nephropathy (DN). The activation of SphK1-S1P pathway by high glucose (HG) can increase the expression of fibronectin (FN), an important fibrotic component, in glomerular mesangial cells (GMCs) by promoting the DNA-binding activity of transcription factor AP-1. However, the mechanism responsible for the sustained activation of SphK1-S1P pathway remains unclear. Given the binding motifs for AP-1 within the first intron of the SphK1 gene, we speculated that the activated AP-1 in the kidney under HG condition possibly regulates SphK1 expression in a positive feedback manner, thereby promoting the sustained activation of SphK1-S1P pathway and mediating the pathological progression of DN. Here, we observed the effect of AP-1 on SphK1 expression in GMCs and explored the molecular mechanism involved in the sustained activation of SphK1-S1P pathway. We found two consensus binding motifs for AP-1 in the promoter sequences and non-coding region downstream of the transcriptional initiation of the rat SphK1 gene by chromatin immunoprecipitation assay. The treatment of GMCs with both HG and S1P significantly increased the protein expression of c-Jun and c-Fos, and obviously enhanced the phosphorylation of c-Jun at Ser63 and Ser73, and c-Fos at Ser32. Knockdown of c-Jun and c-Fos with siRNAs substantially inhibited the expression of SphK1 and FN, whereas overexpression of c-Jun and c-Fos significantly increased the expression of SphK1 and FN. Curcumin treatment greatly decreased the levels of c-Jun, c-Fos, SphK1, and FN in the kidney tissues of diabetic rats. SiRNAs targeting SphK1 and S1P2 receptor respectively inhibited the phosphorylation of c-Jun (ser63 and ser73) and c-Fos (ser32), as well as FN expression under both normal and HG conditions. Our data demonstrated that the activated SphK1-S1P signaling pathway in GMCs under diabetic conditions is closely associated with AP-1 to form a positive feedback loop. This positive feedback loop functions as an important molecular basis for the sustained activation of SphK1-S1P pathway and increased FN expression that lead to the initiation and progression of DN.

Topics: Animals; Binding Sites; Cells, Cultured; Curcumin; Diabetes Mellitus; Diabetic Nephropathies; DNA-Binding Proteins; Enzyme Inhibitors; Fibronectins; Glucose; JNK Mitogen-Activated Protein Kinases; Lysophospholipids; Male; Mesangial Cells; Phosphorylation; Phosphotransferases (Alcohol Group Acceptor); Promoter Regions, Genetic; Protein Binding; Proto-Oncogene Proteins c-fos; Rats; Receptors, Lysosphingolipid; RNA Interference; RNA, Small Interfering; Signal Transduction; Sphingosine; Sweetening Agents; Transcription Factor AP-1

Curcumin, a major polyphenol from the golden spice Curcuma longa commonly known as turmeric, has been recently discovered to have renoprotective effects on diabetic nephropathy (DN). However, the mechanisms underlying these effects remain unclear. We previously demonstrated that the sphingosine kinase 1-sphingosine 1-phosphate (SphK1-S1P) signaling pathway plays a pivotal role in the pathogenesis of DN. This study aims to investigate whether the renoprotective effects of curcumin on DN are associated with its inhibitory effects on the SphK1-S1P signaling pathway. Our results demonstrated that the expression and activity of SphK1 and the production of S1P were significantly down-regulated by curcumin in diabetic rat kidneys and glomerular mesangial cells (GMCs) exposed to high glucose (HG). Simultaneously, SphK1-S1P-mediated fibronectin (FN) and transforming growth factor-beta 1 (TGF-β1) overproduction were inhibited. In addition, curcumin dose dependently reduced SphK1 expression and activity in GMCs transfected with SphK(WT) and significantly suppressed the increase in SphK1-mediated FN levels. Furthermore, curcumin inhibited the DNA-binding activity of activator protein 1 (AP-1), and c-Jun small interference RNA (c-Jun-siRNA) reversed the HG-induced up-regulation of SphK1. These findings suggested that down-regulation of the SphK1-S1P pathway is probably a novel mechanism by which curcumin improves the progression of DN. Inhibiting AP-1 activation is one of the therapeutic targets of curcumin to modulate the SphK1-S1P signaling pathway, thereby preventing diabetic renal fibrosis.

Topics: Animals; Antioxidants; Cells, Cultured; Curcumin; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Drug Evaluation, Preclinical; Fibronectins; Gene Expression; Glucose; JNK Mitogen-Activated Protein Kinases; Kidney; Lysophospholipids; Male; Mesangial Cells; Phosphotransferases (Alcohol Group Acceptor); Rats; Rats, Sprague-Dawley; Signal Transduction; Sphingosine; Transcription Factor AP-1; Transforming Growth Factor beta1

The pro-fibrotic connective tissue growth factor (CTGF) has been linked to the development and progression of diabetic vascular and renal disease. We recently reported that low-density lipoproteins (LDL) induced expression of CTGF in aortic endothelial cells. However, the molecular mechanisms are not fully defined. Here, we have studied the mechanism by which LDL regulates CTGF expression in renal mesangial cells. In these cells, treatment with pertussis toxin abolished LDL-stimulated activation of ERK1/2 and c-Jun N-terminal kinase (JNK), indicating the involvement of heterotrimeric G proteins in LDL signaling. Treatment with LDL promoted activation and translocation of endogenous sphingosine kinase 1 (SK1) from the cytosol to the plasma membrane concomitant with production of sphingosine-1-phosphate (S1P). Pretreating cells with SK inhibitor, dimethylsphinogsine or down-regulation of SK1 and SK2 revealed that LDL-dependent activation of ERK1/2 and JNK is mediated by SK1. Using a green fluorescent protein-tagged S1P₁ receptor as a biological sensor for the generation of physiologically relevant S1P levels, we found that LDL induced S1P receptor activation. Pretreating cells with S1P₁/S1P₃ receptor antagonist VPC23019 significantly inhibited activation of ERK1/2 and JNK by LDL, suggesting that LDL elicits G protein-dependent activation of ERK1/2 and JNK by stimulating SK1-dependent transactivation of S1P receptors. Furthermore, S1P stimulation induced expression of CTGF in a dose-dependent manner that was markedly inhibited by blocking the ERK1/2 and JNK signaling pathways. LDL-induced CTGF expression was pertussis toxin sensitive and inhibited by dimethylsphinogsine down-regulation of SK1 and VPC23019 treatment. Our data suggest that SK1-dependent S1P receptor transactivation is upstream of ERK1/2 and JNK and that all three steps are required for LDL-regulated expression of CTGF in mesangial cells.

Topics: Animals; Cell Membrane; Cells, Cultured; Connective Tissue Growth Factor; Diabetic Nephropathies; Dyslipidemias; Gene Silencing; Humans; Lipoproteins, LDL; Lysophospholipids; MAP Kinase Signaling System; Mesangial Cells; Phosphotransferases (Alcohol Group Acceptor); Protein Isoforms; Protein Transport; Rats; Receptors, Lysosphingolipid; Recombinant Fusion Proteins; RNA, Messenger; RNA, Small Interfering; Sphingosine; Sphingosine-1-Phosphate Receptors; Transcriptional Activation; Up-Regulation

Sphingosine kinase 1 (SphK1) pathway is critical in the pathogenesis of diabetic nephropathy. Recently, we found that berberine suppressed the activation of SphK1 pathway in diabetic kidney, protecting against diabetic nephropathy. The potential molecular mechanism, however, is still unknown. Here, we showed that berberine prevented the expression of α-smooth muscle actin (α-SMA), transforming growth factor-β1 (TGF-β1) and fibronectin (FN) in mesangial cells cultured by high glucose. Furthermore, berberine suppressed the activation of SphK1 pathway via inhibition of the activity and expression of SphK1 in mesangial cells cultured by high glucose. Surprisingly, berberine blocked the increased activity and expression of SphK1 in mesangial cells transfected by wild type SphK1 under normal glucose condition. However, berberine had no inhibitory effect on the recombinant human SphK1 protein. Finally, berberine markedly attenuated the high glucose-induced activator protein-1 (AP-1) activity in mesangial cells. Altogether, these data not only demonstrate that berberine is an important agent against diabetic nephropathy through inhibition of SphK1/AP-1 pathway, but also indicate that the inhibition of SphK1/AP-1 by berberine is independent of ambient glucose concentration.

Topics: Actins; Animals; Berberine; Cells, Cultured; Diabetic Nephropathies; Dose-Response Relationship, Drug; Down-Regulation; Fibronectins; Glucose; Humans; Hypertrophy; Mesangial Cells; Phosphotransferases (Alcohol Group Acceptor); Protein Kinase Inhibitors; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Signal Transduction; Transcription Factor AP-1; Transfection; Transforming Growth Factor beta1

Sphingosine 1-phosphate (S1P), a pleiotropic lipid mediator, binds to five related G-protein-coupled receptors to exert its effects. As S1P1 receptor (S1P1R) activation blocks kidney inflammation in acute renal injury, we tested whether activation of S1P1Rs ameliorates renal injury in early-stage diabetic nephropathy (DN) in rats. Urinary albumin excretion increased in vehicle-treated diabetic rats (single injection of streptozotocin), compared with controls, and was associated with tubule injury and increased urinary tumor necrosis factor-α (TNF-α) at 9 weeks. These effects were significantly reduced by FTY720, a non-selective, or SEW2871, a selective S1P1R agonist. Interestingly, only FTY720 was associated with reduced total lymphocyte levels. Albuminuria was reduced by SEW2871 in both Rag-1 (T- and B-cell deficient) and wild-type diabetic mice after 6 weeks, suggesting that the effect was independent of lymphocytes. Another receptor, S1P3R, did not contribute to the FTY720-mediated protection, as albuminuria was also reduced in diabetic S1P3R knockout mice. Further, both agonists restored WT-1 staining along with podocin and nephrin mRNA expression, suggesting podocyte protection. This was corroborated in vitro, as SEW2871 reduced TNF-α and vascular endothelial growth factor mRNA expression in immortalized podocytes grown in media containing high glucose. Whether targeting kidney S1P1Rs will be a useful therapeutic measure in DN will need direct testing.

Topics: Animals; Cells, Cultured; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Fingolimod Hydrochloride; Kidney; Lymphocytes; Mice; Mice, Inbred C57BL; Oxadiazoles; Phosphotransferases (Alcohol Group Acceptor); Podocytes; Propylene Glycols; Rats; Rats, Sprague-Dawley; Receptors, Lysosphingolipid; Sphingosine; Thiophenes; Tumor Necrosis Factor-alpha

Diabetic nephropathy is characterized by accumulation of glomerular extracellular matrix proteins, such as fibronectin (FN). Here, we investigated whether sphingosine kinase (SphK)1 pathway is responsible for the elevated FN expression in diabetic nephropathy. The SphK1 pathway and FN expression were examined in streptozotocin-induced diabetic rat kidney and glomerular mesangial cells (GMC) exposed to high glucose (HG). FN up-regulation was concomitant with activation of the SphK1 pathway as reflected in an increase in the expression and activity of SphK1 and sphingosine 1-phosphate (S1P) production in both diabetic kidney and HG-treated GMC. Overexpression of wild-type SphK1 (SphK(WT)) significantly induced FN expression, whereas treatment with a SphK inhibitor, N,N-dimethylsphingosine, or transfection of SphK1 small interference RNA or dominant-negative SphK1 (SphK(G82D)) abolished HG-induced FN expression. Furthermore, addition of exogenous S1P significantly induced FN expression in GMC with an induction of activator protein 1 (AP-1) activity. Inhibition of AP-1 activity by curcumin attenuated the S1P-induced FN expression. Finally, by inhibiting SphK1 activity, both N,N-dimethylsphingosine and SphK(G82D) markedly attenuated the HG-induced AP-1 activity. Taken together, these results demonstrated that the SphK1 pathway plays a critical role in matrix accumulation in GMC under diabetic condition, suggesting that the SphK1 pathway could be a potential therapeutic target for diabetic nephropathy.

Topics: Animals; Blood Glucose; Cells, Cultured; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Extracellular Matrix; Fibronectins; Gene Expression; Gene Knockdown Techniques; Glucose; Kidney Glomerulus; Lysophospholipids; Male; Mesangial Cells; Phosphotransferases (Alcohol Group Acceptor); Proteinuria; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Receptors, Lysosphingolipid; RNA Interference; Signal Transduction; Sphingosine; Transcription Factor AP-1

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

In this study, the effects of short-term diabetes (4 days) on rat renal glomerular cells proliferation and the potential involvement of sphingolipids in this process were investigated. Immunohistochemical analysis showed that streptozotocin (STZ)-induced diabetes promoted increased intra-glomerular hyperplasia, particularly marked for mesangial cells. This was associated with a concomitant increase in neutral ceramidase and sphingosine-kinase activities and the accumulation of the pro-proliferative sphingolipid sphingosine-1-phosphate, in glomeruli isolated from kidney cortex of STZ-treated rats. These results suggest a possible involvement of sphingolipid metabolites in the glomerular proliferative response during the early stages of diabetic nephropathy.

Topics: Amidohydrolases; Animals; Cell Proliferation; Ceramidases; Diabetic Nephropathies; Kidney Glomerulus; Lysophospholipids; Male; Neutral Ceramidase; Phosphotransferases (Alcohol Group Acceptor); Rats; Rats, Wistar; Sphingosine; Streptozocin; Time Factors