Inhibition of histone deacetylase activates side population cells in kidney and partially reverses chronic renal injury
Inhibition of histone deacetylase activates side population cells in kidney and partially reverses chronic renal injury
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DOI：
10.1634/stemcells.2007-0049
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发表时间：
2007-01-01
期刊：
影响因子：
5.2
通讯作者：
Fujita, Toshiro
中科院分区：
文献类型：
--
作者：
Imai, Naohiko;Hishikawa, Keiichi;Fujita, Toshiro
骨形态发生蛋白（BMP）-7在成人肾脏中表达，当外源性给予时可逆转慢性肾损伤。在这里，我们报告，组蛋白去乙酰化酶抑制剂，抑制素A（TSA），减轻慢性肾损伤，在一定程度上，通过增加BMP-7在肾侧群体（SP）细胞的表达。我们在C57 BL/6小鼠中诱导加速性肾毒性血清肾炎（NTN），并用TSA治疗3周。与溶剂处理的NTN小鼠相比，TSA处理防止了蛋白尿、肾小球硬化、间质纤维化和肾脏SP细胞损失的进展。与非SP细胞相比，肾SP细胞中肾保护因子如BMP-7、血管内皮生长因子和肝细胞生长因子的基础基因表达显著升高。TSA处理显著上调SP细胞中BMP-7的表达，但在非SP细胞中不上调。此外，NTN治疗3周后开始TSA治疗（持续3周，直至6周）部分但显著逆转了肾功能不全。我们的研究结果表明，SP细胞在肾脏中的重要作用，作为一个可能的发电机细胞的BMP-7和TSA作为刺激的细胞在逆转慢性肾脏疾病。
Bone morphogenic protein ( BMP)-7 is expressed in the adult kidney and reverses chronic renal injury when given exogenously. Here, we report that a histone deacetylase inhibitor, trichostatin A ( TSA), attenuates chronic renal injury, in part, by augmenting the expression of BMP-7 in kidney side population ( SP) cells. We induced accelerated nephrotoxic serum nephritis ( NTN) in C57BL/6 mice and treated them with TSA for 3 weeks. Compared with vehicle-treated NTN mice, treatment with TSA prevented the progression of proteinuria, glomerulosclerosis, interstitial fibrosis, and loss of kidney SP cells. Basal gene expression of renoprotective factors such as BMP-7, vascular endothelial growth factor, and hepatocyte growth factor was significantly higher in kidney SP cells as compared with non-SP cells. Treatment with TSA significantly upregulated the expression of BMP-7 in SP cells but not in non-SP cells. Moreover, initiation of treatment with TSA after 3 weeks of NTN ( for 3 weeks, until 6 weeks) partially but significantly reversed renal dysfunction. Our results indicate an important role of SP cells in the kidney as one of the possible generator cells of BMP-7 and TSA as a stimulator of the cells in reversing chronic renal disease.