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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1338-1350
Number of pages13
JournalAmerican Journal of Pathology
Volume189
Issue number7
DOIs
Publication statusPublished - 01-07-2019

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CD147 Antigens
Podocytes
Wounds and Injuries
Kidney Diseases
Transforming Growth Factors
Metalloproteases
Proteinuria
Physiological Feedback
Focal Segmental Glomerulosclerosis
Focal Adhesions
Endothelin-1
Doxorubicin
Vascular Endothelial Growth Factor A
Cell Movement
Names
Arginine

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

Cite this

Yoshioka, T., Kosugi, T., Masuda, T., Watanabe, T., Ryuge, A., Nagaya, H., ... Kadomatsu, K. (2019). CD147/Basigin Deficiency Prevents the Development of Podocyte Injury through FAK Signaling. American Journal of Pathology, 189(7), 1338-1350. https://doi.org/10.1016/j.ajpath.2019.04.003
Yoshioka, Tomoki ; Kosugi, Tomoki ; Masuda, Tomohiro ; Watanabe, Tomoharu ; Ryuge, Akihiro ; Nagaya, Hiroshi ; Maeda, Kayaho ; Sato, Yuka ; Katsuno, Takayuki ; Kato, Noritoshi ; Ishimoto, Takuji ; Yuzawa, Yukio ; Maruyama, Shoichi ; Kadomatsu, Kenji. / CD147/Basigin Deficiency Prevents the Development of Podocyte Injury through FAK Signaling. In: American Journal of Pathology. 2019 ; Vol. 189, No. 7. pp. 1338-1350.
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Yoshioka, T, Kosugi, T, Masuda, T, Watanabe, T, Ryuge, A, Nagaya, H, Maeda, K, Sato, Y, Katsuno, T, Kato, N, Ishimoto, T, Yuzawa, Y, Maruyama, S & Kadomatsu, K 2019, 'CD147/Basigin Deficiency Prevents the Development of Podocyte Injury through FAK Signaling', American Journal of Pathology, vol. 189, no. 7, pp. 1338-1350. https://doi.org/10.1016/j.ajpath.2019.04.003

CD147/Basigin Deficiency Prevents the Development of Podocyte Injury through FAK Signaling. / Yoshioka, Tomoki; Kosugi, Tomoki; Masuda, Tomohiro; Watanabe, Tomoharu; Ryuge, Akihiro; Nagaya, Hiroshi; Maeda, Kayaho; Sato, Yuka; Katsuno, Takayuki; Kato, Noritoshi; Ishimoto, Takuji; Yuzawa, Yukio; Maruyama, Shoichi; Kadomatsu, Kenji.

In: American Journal of Pathology, Vol. 189, No. 7, 01.07.2019, p. 1338-1350.

Research output: Contribution to journalArticle

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T1 - CD147/Basigin Deficiency Prevents the Development of Podocyte Injury through FAK Signaling

AU - Yoshioka, Tomoki

AU - Kosugi, Tomoki

AU - Masuda, Tomohiro

AU - Watanabe, Tomoharu

AU - Ryuge, Akihiro

AU - Nagaya, Hiroshi

AU - Maeda, Kayaho

AU - Sato, Yuka

AU - Katsuno, Takayuki

AU - Kato, Noritoshi

AU - Ishimoto, Takuji

AU - Yuzawa, Yukio

AU - Maruyama, Shoichi

AU - Kadomatsu, Kenji

PY - 2019/7/1

Y1 - 2019/7/1

N2 - 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.

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