Abstract: FR-PO375
Leukaemia Inhibitory Factor Promotes Fibroblast Activation via ERK-Egr-1 Pathway and Increasing Mitochondrial Biogenesis
Session Information
- CKD: Mechanisms - II
November 08, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2103 CKD (Non-Dialysis): Mechanisms
Authors
- Xu, Shihui, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guang Zhou, China
- Su, Zhiyuan, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guang Zhou, China
- Zhou, Miaomiao, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guang Zhou, China
- Zhu, Fengxin, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guang Zhou, China
- Nie, Jing, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guang Zhou, China
Background
Fibrosis is the common pathway of various progressive kidney diseases. Fibroblasts are major players in the pathogenesis of renal fibrosis. Recent researches have shown that Leukemia Inhibitory Factor (LIF) exerts beneficial effects on various diseases. However, the role of LIF in the pathogenesis of kidney diseases remains largely unknown. Our study is to investigate the role of LIF in renal fibrosis.
Methods
Animal model of renal fibrosis was induced by unilateral ureteral occlusion (UUO) and ischemia reperfusion injury (IRI). Western blot (WB) and real time PCR were performed to evaluate the expression of LIF, LIF receptor (LIFR) and GP130, etc. Immunofluorescence staining was performed to evaluate the localization of LIF, LIFR and GP130. LIF neutralizing antibody was subcutaneously injected to evaluate the role of LIF in renal fibrosis induced by UUO. H&E, Masson and Sirius red staining were used to estimate renal pathology. Transforming growth factor β1 (TGF-β1) was used to stimulate cultured NRK-49F cells and primary mouse fibroblasts.
Results
LIF and its receptors (LIFR and GP130) were mainly expressed in interstitial fibroblasts, and significantly upregulated in fibrotic renal tissues induced by both UUO and IRI. LIF promoted the activation and proliferation of both NRK-49F cells and primary mouse fibroblasts through ERK-Egr-1 pathway. ERK inhibitor U0126 or silencing endogenous Egr-1 significantly inhibited LIF-induced fibroblast activation in NRK-49F cells. LIF stimulates mitochondrial biogenesis in both NRK-49F cells and primary mouse fibroblasts. LIF neutralizing antibody significantly inhibited TGF-β induced fibroblast activation in vitro, attenuated interstitial fibrosis induced by UUO.
Conclusion
Our experimental results indicate that LIF-LIFR/GP130-ERK-Egr-1 pathway plays a detrimental role in fibroblasts activation and thus contributes to interstitial fibrosis. LIF stimulates mitochondrial biogenesis to promote the activation and proliferation of both NRK-49F cells and primary mouse fibroblasts. Blocking LIF production is a plausible strategy for therapeutic intervention of chronic kidney disorders.
Funding
- Government Support - Non-U.S.