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Int. J. Mol. Sci. 2017, 18(8), 1795; doi:10.3390/ijms18081795

Rho-Kinase Blockade Attenuates Podocyte Apoptosis by Inhibiting the Notch Signaling Pathway in Diabetic Nephropathy

Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, Tokyo 105-8461, Japan
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Received: 18 July 2017 / Revised: 14 August 2017 / Accepted: 15 August 2017 / Published: 18 August 2017
(This article belongs to the Special Issue Advances in Chronic Kidney Disease 2017)
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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. View Full-Text
Keywords: Rho-kinase; Jag1; Notch signaling; diabetic nephropathy Rho-kinase; Jag1; Notch signaling; diabetic nephropathy
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MDPI and ACS Style

Matoba, K.; Kawanami, D.; Nagai, Y.; Takeda, Y.; Akamine, T.; Ishizawa, S.; Kanazawa, Y.; Yokota, T.; Utsunomiya, K. Rho-Kinase Blockade Attenuates Podocyte Apoptosis by Inhibiting the Notch Signaling Pathway in Diabetic Nephropathy. Int. J. Mol. Sci. 2017, 18, 1795.

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