Glomerular proliferation during early stages of diabetic nephropathy is associated with local increase of sphingosine‐1‐phosphate levels

Geoffroy, Karen; Troncy, Lysiane; Wiernsperger, Nicolas; Lagarde, Michel; Bawab, Samer El

doi:10.1016/j.febslet.2004.12.094

Cited by 80 publications

(68 citation statements)

References 25 publications

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“…In general, diabetic nephropathy advances from the glomerular hyperfiltration stage to the glomerular sclerotic stage with reduced glomerular filtration. It has been proposed that SPHK1/ S1P contributes to the early stages of diabetic nephropathy as diabetes enhances SPHK1 activity, which results in an increased mesangial cell proliferation, a key event in pathogenesis of the disease [32,33]. To determine whether Ad-SPHK1 infection could exacerbate the diabetes-induced renal structural damage or not, we observed the renal structural changes in both groups.…”

Section: Resultsmentioning

confidence: 99%

Sphingosine kinase 1 participates in insulin signalling and regulates glucose metabolism and homeostasis in KK/Ay diabetic mice

Chen²,

Wang³

et al. 2007

Diabetologia

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Aims/hypothesis The aim of this study was to determine the potential role of sphingosine kinase 1 (SPHK1), a key sphingolipid metabolic enzyme, in glucose metabolism and homeostasis. Methods SMMC-7721 hepatoma cells and C2C12 myotube cells were used to explore the role of SPHK1 in glucose uptake in vitro. KK/Ay type 2 diabetic mice, which were transfected with adenovirus harbouring the human SPHK1 gene by i.v. injection, were used to investigate the glucoselowering effects of SPHK1 in vivo.Results The basal glucose uptake and the insulin-stimulated glucose uptake in both 7721 cells and C2C12 cells were markedly enhanced when SPHK1 was overexpressed by adenovirus-mediated gene transfer, whereas they were substantially reduced when the expression of SPHK1 was inhibited or the activity of SPHK1 was blocked. Insulin could activate SPHK1 of both cell lines in a dosedependent manner. SPHK1 gene delivery significantly reduced the blood glucose level of KK/Ay diabetic mice, but had no effect on that of normal animals. It also attenuated elevated levels of plasma insulin, NEFA, triacylglycerol, cholesterol and LDL, significantly ameliorated hyperglycaemia-induced injury of liver, heart and kidney, and enhanced phosphorylation of insulin-signalling kinases such as Akt and glycogen synthase kinase 3β in livers of the diabetic animals. Conclusions/interpretation SPHK1 is involved in insulin signalling and plays an important role in the regulation of glucose and fat metabolism; adenovirus-mediated SPHK1 gene transfer might provide a novel strategy in the treatment of type 2 diabetes mellitus.

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Section: Resultsmentioning

confidence: 99%

Sphingosine kinase 1 participates in insulin signalling and regulates glucose metabolism and homeostasis in KK/Ay diabetic mice

Chen²,

Wang³

et al. 2007

Diabetologia

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“…There is a two-stage renal growth response, with early proliferation and subsequent hypertrophy. Renal cell proliferation appears very soon after the onset of diabetes [2, 15]. Although this early event is crucial for the initiation of diabetic nephropathy, it is transient and self-limited because the cell cycle is arrested in G0/G1 phase in the presence of potent inhibitors of cell cycle progression, such as CdK inhibitors, P21 Cip1 and P27 Kip1 , which are induced by high glucose levels [1].…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, the hyperplasia of the renal cells that we described above was obviously reduced by rapamycin treatment, although its overexpression was slight in the diabetic kidney, especially in the glomeruli. Therefore, it can be hypothesized that the very early prominent glomerular and tubular cell proliferation, crucial for the initiation of diabetic nephropathy [15], should be strongly inhibited by rapamycin too. Another work should be done to confirm this idea.…”

Section: Discussionmentioning

confidence: 99%

“…Lloberas et al [14] reported that mTOR blockade by low-dose rapamycin had a beneficial effect in diabetic kidney disease. Since some events, such as mesangial cell proliferation and macrophage recruitment occurring very early in the kidney after onset of diabetes, played a pivotal role in initiation and progression of diabetic nephropathy [15, 16], we postulated that rapamycin treatment performed during the course of diabetes would halt the early steps of the development of diabetic nephropathy and lead to more therapeutic benefit.…”

Section: Introductionmentioning

confidence: 99%

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Rapamycin Prevents Early Steps of the Development of Diabetic Nephropathy in Rats

Yang¹,

Wang²,

Ling³

et al. 2007

Am J Nephrol

161

122

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Background/Aims: Recent studies suggested the involvement of the Akt/mammalian target of rapamycin (mTOR) pathway in the pathogenesis of diabetic nephropathy. The effect of mTOR blockade by rapamycin in diabetic nephropathy was investigated, but in vivo study of rapamycin treatment in the course of early diabetes is still insufficient. This study was designed to determine the therapeutic effects of rapamycin on diabetic nephropathy at an early stage. Methods: Diabetes was induced in Sprague-Dawley rats with streptozotocin, and rapamycin (1 mg/kg) was administered by daily gavage for 4 weeks. Renal structural changes and some factors involved in the early pathogenesis of diabetic nephropathy were tested. The activation level of the Akt/mTOR pathway was also determined. Results: Rapamycin treatment reduced albuminuria, glomerular enlargement, glomerular basement membrane thickening, renal macrophage recruitment, and levels of renal mRNA expression of proliferating cell nuclear antigen, transforming growth factor-β₁, vascular endothelial growth factor, and monocyte chemoattractant protein-1 without change in blood glucose level and blood pressure in experimental diabetic rats. In addition, treatment with rapamycin also down-regulated the enhanced levels of renal p-Akt, phospho-p70S6 kinase, and phospho-ribosomal S6 protein in diabetic rats. Conclusions: Rapamycin treatment can prevent the early renal structural changes of diabetes in experimental rats, and thus halt the early steps of the development of diabetic nephropathy. mTOR blockade might be beneficial for the treatment of diabetic nephropathy.

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“…Several studies report that S1P signaling has a potent influence on the renal response to ischemia-reperfusion injury (4,16,18), mesangial cell function, and the progression of diabetic nephropathy (13,14,19,37). The regulation and function of S1P during kidney development, however, have not been previously reported.…”

mentioning

confidence: 86%

Dynamic regulation of sphingosine-1-phosphate homeostasis during development of mouse metanephric kidney

Kirby

Jin

et al. 2009

American Journal of Physiology-Renal Physiology

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Branching morphogenesis of the metanephric kidney is critically dependent on the delicate orchestration of diverse cellular processes including proliferation, apoptosis, migration, and differentiation. Sphingosine-1-phosphate (S1P) is a potent lipid mediator influencing many of these cellular events. We report increased expression and activity of both sphingosine kinases and S1P phosphatases during development of the mouse metanephric kidney from induction at embryonic day 11.5 to maturity. Sphingosine kinase activity exceeded S1P phosphatase activity in embryonic kidneys, resulting in a net accumulation of S1P, while kinase and phosphatase activities were similar in adult tissue, resulting in reduced S1P content. Sphingosine kinase expression was greater in the metanephric mesenchyme than in the ureteric bud, while the S1P phosphatase SPP2 was expressed at greater levels in the ureteric bud. Treatment of cultured embryonic kidneys with sphingosine kinase inhibitors resulted in a dose-dependent reduction of ureteric bud tip numbers and increased apoptosis. Exogenous S1P rescued kidneys from apoptosis induced by kinase inhibitors. Ureteric bud tip number was unaffected by exogenous S1P in kidneys treated with N,Ndimethylsphingosine, although tip number increased in those treated with D,L-threo-dihydrosphingosine. S1P1 and S1P2 were the predominant S1P receptors expressed in the embryonic kidney. S1P1 expression increased during renal development while expression of S1P2 decreased, and both receptors were expressed predominantly in the metanephric mesenchyme. These results demonstrate dynamic regulation of S1P homeostasis during renal morphogenesis and suggest that differential expression of S1P metabolic enzymes and receptors provides a novel mechanism contributing to the regulation of kidney development. renal morphogenesis; sphingolipid; kinase; phosphatase; receptor DEVELOPMENT OF THE METANEPHRIC kidney is a highly complex event orchestrated by numerous factors regulating proliferation, migration, and differentiation of individual cell types to form the functional kidney. This process is initiated by induction of the ureteric bud, an outgrowth of the Wolffian duct, by the metanephric mesenchyme. Subsequent branching of the ureteric bud induces mesenchymal-to-epithelial transformation and nephron formation. Inductive interactions between the ureteric bud epithelia and the metanephric mesenchyme are mediated by a multitude of stimulatory and inhibitory factors (7,42). Failure of mechanisms regulating normal kidney development can result in a variety of congenital defects and may contribute to nephron deficiencies leading to development of hypertension and renal failure.Sphingosine-1-phosphate (S1P) is a potent bioactive lipid that functions both as an intracellular second messenger promoting cell survival and proliferation and as a ligand for G proteincoupled cell surface receptors (S1PRs) to influence migration and differentiation. S1P has a powerful influence on developmental processes, and recent studies have...

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Glomerular proliferation during early stages of diabetic nephropathy is associated with local increase of sphingosine‐1‐phosphate levels

Cited by 80 publications

References 25 publications

Sphingosine kinase 1 participates in insulin signalling and regulates glucose metabolism and homeostasis in KK/Ay diabetic mice

Sphingosine kinase 1 participates in insulin signalling and regulates glucose metabolism and homeostasis in KK/Ay diabetic mice

Rapamycin Prevents Early Steps of the Development of Diabetic Nephropathy in Rats

Dynamic regulation of sphingosine-1-phosphate homeostasis during development of mouse metanephric kidney

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