Abstract: SA-PO821
cMet Agonistic Antibody Attenuates Renal Fibrosis in Obstructive Nephropathy
Session Information
- Molecular Mechanisms of CKD - III
October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 1903 CKD (Non-Dialysis): Mechanisms
Authors
- Kim, Yong Chul, SNUH, Seoul, Korea (the Republic of)
- An, Jung Nam, Seoul National University Boramae Medical Center, Seoul, SEOUL, Korea (the Republic of)
- Lim, Chun Soo, Seoul National University Boramae Medical Center, Seoul, SEOUL, Korea (the Republic of)
- Kim, Yon Su, Seoul National University College of Medicine, Seoul, Korea (the Republic of)
- Yang, Seung Hee, Kidney Research Institute, Seoul National University, Seoul, Korea (the Republic of)
- Lee, Jung Pyo, Seoul National University Boramae Medical Center, Seoul, SEOUL, Korea (the Republic of)
Background
Hepatocyte growth factor (HGF) and its receptor, cMet, activate biological pathways necessary for repair and regeneration following kidney injury. The Met receptor is expressed in multiple cell types within the kidney, each of which is capable of regulating fibrotic responses. Since HGF is a quite unstable molecule in its biologically active form, we asked whether a monoclonal antibody (Ab) that displays receptor full agonist activity could protect kidney from fibrosis.
Methods
We tried to determine whether cMet agonistic Ab might reduce fibrosis, the final common pathway for chronic kidney diseases. We primary cultured human proximal tubular epithelial cells (PTECs) for in vitro study and a mouse model of renal fibrosis disease induced by unilateral ureteral obstruction (UUO) was introduced.
Results
In kidney biopsy specimens of CKD patients, cMet immunohistochemistry staining showed remarkable increase than patients with normal renal functions. cMet Ab treatment significantly increased phospho-cMet expression and abrogated protein expressions of fibrosis markers such as fibronectin, collagen IV, αSMA and also Bax2 which is a marker of apoptosis triggered by recombinant TGF-β1 in PTECs. In a wound healing scratch assay, PTECs treated with cMet Ab progressed into the wound area more rapidly inducing wound healing than untreated cells. Remarkably, injections of cMet Ab significantly prevented renal fibrosis in the obstructed kidneys quantified by Masson Trichrome staining. Consistently, cMet Ab decreased the expression of fibrosis markers such as, collagen 1 and αSMA, and E-cadherin which is a cell-to-cell adhesion molecule was recovered.
Conclusion
cMet-mediated signaling may have a considerable role in the renal fibrosis. And cMet agonistic Ab may thus be a valuable substitute for HGF, being more easily available in a biologically active, stabilized, and purified form.