Renoprotective effects of a novel cMet agonistic antibody on kidney fibrosis

Yong Chul Kim, Junghun Lee, Jung Nam An, Jin Hyuk Kim, Young Wook Choi, Lilin Li, Sang Ho Kwon, Mi Young Lee, Boeun Lee, Jae Gyun Jeong, Seung Shin Yu, Chun Soo Lim, Yon Su Kim, Sunyoung Kim, Seung Hee Yang, Jung Pyo Lee

Research output: Contribution to journalArticle

Abstract

Hepatocyte growth factor (HGF) and its receptor, cMet, activate biological pathways necessary for repair and regeneration following kidney injury. Because HGF is a highly unstable molecule in its biologically active form, we asked whether a monoclonal antibody (Ab) that displays full agonist activity at the receptor could protect the kidney from fibrosis. We attempted to determine whether the cMet agonistic Ab might reduce fibrosis, the final common pathway for chronic kidney diseases (CKD). A mouse model of kidney fibrosis disease induced by unilateral ureteral obstruction was introduced and subsequently validated with primary cultured human proximal tubular epithelial cells (PTECs). In kidney biopsy specimens from patients with CKD, cMet immunohistochemistry staining showed a remarkable increase compared with patients with normal renal functions. cMet Ab treatment significantly increased the levels of phospho-cMet and abrogated the protein expression of fibrosis markers such as fibronectin, collagen 1, and αSMA as well as Bax2, which is a marker of apoptosis triggered by recombinant TGF-β1 in PTECs. Remarkably, injections of cMet Ab significantly prevented kidney fibrosis in obstructed kidneys as quantified by Masson trichrome staining. Consistent with these data, cMet Ab treatment decreased the expression of fibrosis markers, such as collagen1 and αSMA, whereas the expression of E-cadherin, which is a cell-cell adhesion molecule, was restored. In conclusion, cMet-mediated signaling may play a considerable role in kidney fibrosis. Additionally, the cMet agonistic Ab may be a valuable substitute for HGF because it is more easily available in a biologically active, stable, and purified form.

Original languageEnglish
Article number13495
JournalScientific Reports
Volume9
Issue number1
DOIs
StatePublished - 1 Dec 2019

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Fibrosis
Kidney
Antibodies
Hepatocyte Growth Factor
Chronic Renal Insufficiency
Epithelial Cells
Proto-Oncogene Proteins c-met
Staining and Labeling
Ureteral Obstruction
Kidney Diseases
Cell Adhesion Molecules
Cadherins
Fibronectins
Regeneration
Collagen
Immunohistochemistry
Monoclonal Antibodies
Apoptosis
Biopsy
Injections

Cite this

Kim, Yong Chul ; Lee, Junghun ; An, Jung Nam ; Kim, Jin Hyuk ; Choi, Young Wook ; Li, Lilin ; Kwon, Sang Ho ; Lee, Mi Young ; Lee, Boeun ; Jeong, Jae Gyun ; Yu, Seung Shin ; Lim, Chun Soo ; Kim, Yon Su ; Kim, Sunyoung ; Yang, Seung Hee ; Lee, Jung Pyo. / Renoprotective effects of a novel cMet agonistic antibody on kidney fibrosis. In: Scientific Reports. 2019 ; Vol. 9, No. 1.
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abstract = "Hepatocyte growth factor (HGF) and its receptor, cMet, activate biological pathways necessary for repair and regeneration following kidney injury. Because HGF is a highly unstable molecule in its biologically active form, we asked whether a monoclonal antibody (Ab) that displays full agonist activity at the receptor could protect the kidney from fibrosis. We attempted to determine whether the cMet agonistic Ab might reduce fibrosis, the final common pathway for chronic kidney diseases (CKD). A mouse model of kidney fibrosis disease induced by unilateral ureteral obstruction was introduced and subsequently validated with primary cultured human proximal tubular epithelial cells (PTECs). In kidney biopsy specimens from patients with CKD, cMet immunohistochemistry staining showed a remarkable increase compared with patients with normal renal functions. cMet Ab treatment significantly increased the levels of phospho-cMet and abrogated the protein expression of fibrosis markers such as fibronectin, collagen 1, and αSMA as well as Bax2, which is a marker of apoptosis triggered by recombinant TGF-β1 in PTECs. Remarkably, injections of cMet Ab significantly prevented kidney fibrosis in obstructed kidneys as quantified by Masson trichrome staining. Consistent with these data, cMet Ab treatment decreased the expression of fibrosis markers, such as collagen1 and αSMA, whereas the expression of E-cadherin, which is a cell-cell adhesion molecule, was restored. In conclusion, cMet-mediated signaling may play a considerable role in kidney fibrosis. Additionally, the cMet agonistic Ab may be a valuable substitute for HGF because it is more easily available in a biologically active, stable, and purified form.",
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Kim, YC, Lee, J, An, JN, Kim, JH, Choi, YW, Li, L, Kwon, SH, Lee, MY, Lee, B, Jeong, JG, Yu, SS, Lim, CS, Kim, YS, Kim, S, Yang, SH & Lee, JP 2019, 'Renoprotective effects of a novel cMet agonistic antibody on kidney fibrosis', Scientific Reports, vol. 9, no. 1, 13495. https://doi.org/10.1038/s41598-019-49756-z

Renoprotective effects of a novel cMet agonistic antibody on kidney fibrosis. / Kim, Yong Chul; Lee, Junghun; An, Jung Nam; Kim, Jin Hyuk; Choi, Young Wook; Li, Lilin; Kwon, Sang Ho; Lee, Mi Young; Lee, Boeun; Jeong, Jae Gyun; Yu, Seung Shin; Lim, Chun Soo; Kim, Yon Su; Kim, Sunyoung; Yang, Seung Hee; Lee, Jung Pyo.

In: Scientific Reports, Vol. 9, No. 1, 13495, 01.12.2019.

Research output: Contribution to journalArticle

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T1 - Renoprotective effects of a novel cMet agonistic antibody on kidney fibrosis

AU - Kim, Yong Chul

AU - Lee, Junghun

AU - An, Jung Nam

AU - Kim, Jin Hyuk

AU - Choi, Young Wook

AU - Li, Lilin

AU - Kwon, Sang Ho

AU - Lee, Mi Young

AU - Lee, Boeun

AU - Jeong, Jae Gyun

AU - Yu, Seung Shin

AU - Lim, Chun Soo

AU - Kim, Yon Su

AU - Kim, Sunyoung

AU - Yang, Seung Hee

AU - Lee, Jung Pyo

PY - 2019/12/1

Y1 - 2019/12/1

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