CD147/Basigin Deficiency Prevents the Development of Podocyte Injury through FAK Signaling.

Abstract

Podocytes, which are susceptible to injury by various stimuli and stress, are critical regulators of proteinuric kidney diseases, regardless of the primary disease and pathogenesis. We further confirmed a significant correlation between urinary CD147/basigin (Bsg) levels and proteinuria in patients with focal segmental glomerulosclerosis. However, the molecular mechanism of podocyte injury involving Bsg is not fully understood. Here, the involvement of Bsg in the pathogenesis of podocyte injury was elucidated. Healthy podocytes rarely express Bsg protein. In two independent mouse models, including adriamycin-induced nephropathy and Nω-nitro-l-arginine methyl ester (l-name)-induced endothelial dysfunction, Bsg induction in injured podocytes caused podocyte effacement, which led to development of proteinuria. Bsg silencing in cultured podocytes exposed to transforming growth factor-β suppressed focal adhesion rearrangement and cellular motility via the activation of β1 integrin-focal adhesion kinase-matrix metallopeptidase signaling. In addition, induction of vascular endothelial growth factor and endothelin-1, which are implicated in podocyte-to-endothelial cross-communication, was lower in the supernatants of cultured Bsg-silenced podocytes stimulated with transforming growth factor-β. In this setting, Bsg may be involved in a physiological positive feedback loop that accelerates podocyte cell motility and depolarization. The current study thus suggests that Bsg silencing via suppression of β1 integrin-focal adhesion kinase-matrix metallopeptidase signaling may be an attractive therapeutic strategy for the maintenance of podocytes in patients with proteinuric kidney diseases.

• Authors: Tomoki Yoshioka, Tomoki Kosugi, Tomohiro Masuda, Tomoharu Watanabe, Akihiro Ryuge, Hiroshi Nagaya, Kayaho Maeda, Yuka Sato, Takayuki Katsuno, Noritoshi Kato, Takuji Ishimoto, Yukio Yuzawa, Shoichi Maruyama, Kenji Kadomatsu
• Journal: The American journal of pathology (Am J Pathol) Vol. 189 Issue 7 Pg. 1338-1350 (07 2019) ISSN: 1525-2191 [Electronic] United States
• PMID: 31014956 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• BSG protein, human
• Bsg protein, mouse
• Basigin
• Doxorubicin
• Focal Adhesion Kinase 1
• PTK2 protein, human
• Ptk2 protein, mouse
• NG-Nitroarginine Methyl Ester

Topics

• Adult
• Animals
• Basigin (deficiency)
• Disease Models, Animal
• Doxorubicin (adverse effects, pharmacology)
• Female
• Focal Adhesion Kinase 1 (metabolism)
• Glomerulosclerosis, Focal Segmental (chemically induced, metabolism, pathology)
• Humans
• Male
• Mice
• Mice, Knockout
• NG-Nitroarginine Methyl Ester (pharmacology)
• Podocytes (metabolism, pathology)
• Proteinuria (chemically induced, metabolism, pathology)
• Signal Transduction