Rho-Kinase Blockade Attenuates Podocyte Apoptosis by Inhibiting the Notch Signaling Pathway in Diabetic Nephropathy.
Rho-Kinase Blockade Attenuates Podocyte Apoptosis by Inhibiting the Notch Signaling Pathway in Diabetic Nephropathy.
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Rho激酶阻断剂通过抑制Notch信号通路减轻糖尿病肾病足细胞凋亡
DOI：
10.3390/ijms18081795
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发表时间：
2017-08-18
影响因子：
5.6
通讯作者：
Utsunomiya K
中科院分区：
文献类型：
--
作者：
Matoba K;Kawanami D;Nagai Y;Takeda Y;Akamine T;Ishizawa S;Kanazawa Y;Yokota T;Utsunomiya K
足细胞凋亡是糖尿病肾病发病的关键过程。大量证据表明，Notch信号通路在这一过程中起着核心作用。我们发现Rho-Kinase介导了转化生长因子β(TGFR-β)诱导的Notch配体Jag1的表达。重要的是，转化生长因子-β介导的足细胞凋亡被Rho-Kinase抑制而减弱。机制上，Rho-Kinase通过细胞外信号调节激酶(ERK)1/2和c-Jun氨基末端激酶(JNK)调节Jag1的诱导，而不是Smad通路。Rho-Kinase抑制剂法舒地尔一直可以预防db/db小鼠的蛋白尿和尿液中neparin的排泄，并减少足细胞凋亡和Jag1的表达。经法舒地尔处理的db/db小鼠足细胞Jag1表达及细胞凋亡标志物Bax和细胞周期蛋白依赖性激酶抑制因子1a(CDKN1a)表达降低。本研究提供了Rho-Kinase在足细胞凋亡中起关键作用的证据。Rho-Kinase是治疗糖尿病肾病的有吸引力的靶点。
Podocyte apoptosis is a key process in the onset of diabetic nephropathy. A significant body of evidence shows that the Notch signaling pathway plays a central role in this process. We found that Rho-kinase mediates transforming growth factor β (TGF-β)-induced Notch ligand Jag1 expression. Importantly, TGF-β-mediated podocyte apoptosis was attenuated by Rho-kinase inhibition. Mechanistically, Rho-kinase regulated Jag1 induction via the extracellular signal-regulated kinase (ERK) 1/2 and c-Jun N-terminal kinase (JNK) but not Smad pathways. Consistently, the Rho-kinase inhibitor fasudil prevented albuminuria and the urinary excretion of nephrin in db/db mice and reduced the prevalence of podocyte apoptosis and Jag1 expression. Finally, the expression of Jag1 and apoptosis markers such as Bax and cyclin-dependent kinase inhibitor 1A (CDKN1A) was decreased in podocytes derived from db/db mice treated with fasudil. The present study provides evidence that Rho-kinase plays a key role in podocyte apoptosis. Rho-kinase is an attractive therapeutic target for diabetic nephropathy.
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