Kirby R Jason, Jin Ying, Fu Jian, Cubillos Jimena, Swertfeger Debi, Arend Lois J
Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio 45267-0529, USA.
Am J Physiol Renal Physiol. 2009 Mar;296(3):F634-41. doi: 10.1152/ajprenal.90232.2008. Epub 2008 Dec 10.
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,N-dimethylsphingosine, 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.
后肾的分支形态发生严重依赖于多种细胞过程的精细协调，包括增殖、凋亡、迁移和分化。鞘氨醇-1-磷酸（S1P）是一种强效脂质介质，影响许多此类细胞事件。我们报告，在小鼠后肾从胚胎第11.5天诱导到成熟的发育过程中，鞘氨醇激酶和S1P磷酸酶的表达和活性均增加。胚胎肾中鞘氨醇激酶活性超过S1P磷酸酶活性，导致S1P净积累，而成体组织中激酶和磷酸酶活性相似，导致S1P含量降低。鞘氨醇激酶在后肾间充质中的表达高于输尿管芽，而S1P磷酸酶SPP2在输尿管芽中的表达水平更高。用鞘氨醇激酶抑制剂处理培养的胚胎肾，导致输尿管芽尖数量呈剂量依赖性减少，并增加凋亡。外源性S1P可使肾脏免受激酶抑制剂诱导的凋亡。在用N，N-二甲基鞘氨醇处理的肾脏中，外源性S1P对输尿管芽尖数量无影响，尽管在用d，l-苏式-二氢鞘氨醇处理的肾脏中芽尖数量增加。S1P1和S1P2是胚胎肾中表达的主要S1P受体。S1P1在肾脏发育过程中表达增加，而S1P2的表达减少，且两种受体主要在后肾间充质中表达。这些结果表明，在肾脏形态发生过程中S1P稳态受到动态调节，并提示S1P代谢酶和受体的差异表达提供了一种有助于调节肾脏发育的新机制。
