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- Title
Rho-Kinase Blockade Attenuates Podocyte Apoptosis by Inhibiting the Notch Signaling Pathway in Diabetic Nephropathy.
- Authors
Keiichiro Matoba; Daiji Kawanami; Yosuke Nagai; Yusuke Takeda; Tomoyo Akamine; Sho Ishizawa; Yasushi Kanazawa; Tamotsu Yokota; Kazunori Utsunomiya
- Abstract
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.
- Subjects
APOPTOSIS; CELL death; DIABETIC nephropathies; NOTCH signaling pathway; CELL communication
- Publication
International Journal of Molecular Sciences, 2017, Vol 18, Issue 8, p1795
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms18081795