Abstract: SA-PO809
The FDA-Approved MEK Inhibitor Trametinib Ameliorates Kidney Fibrosis by Suppressing ERK1/2 and mTORC1 Signalling
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
- Andrikopoulos, Petros, Queen Mary, University of London, London, United Kingdom
- Kieswich, Julius Edward, Queen Mary, University of London, London, United Kingdom
- Pacheco, Sabrina Clare, Queen Mary, University of London, London, United Kingdom
- Nadarajah, Luxme, Queen Mary, University of London, London, United Kingdom
- Harwood, Steven Michael, Queen Mary, University of London, London, United Kingdom
- Yaqoob, Muhammad M., Queen Mary, University of London, London, United Kingdom
Background
The incidence of Chronic Kidney Disease (CKD) is reaching epidemic proportions with rising associated morbidity and mortality. Consequently, there is an urgent need for novel treatments. The ERK1/2 pathway is activated during kidney fibrosis, a hallmark and promoter of CKD irrespective of the underlying cause, and has been detrimentally implicated in the differentiation and expansion of kidney fibroblasts. Trametinib, an ERK1/2-pathway inhibitor has been recently approved for the treatment of melanoma. However, the efficacy of trametinib in the setting of renal fibrosis has not been explored.
Methods
Unilateral Ureteral Obstruction (UUO) was established in male C57BL/6J mice. Trametinib (3mg/Kg) was admisnistered, once daily, by oral gavage for 6 days. or. in a parallel study, 4 days after UUO once daily for six days. Human kidney fibroblasts were from Cambridge Bioscience. Immunoblot was conducted using the NuPAGE system (Invitrogen). Immunostaining was performed with the DISCOVERY XT (Ventana) instrument.
Results
Trametinib significantly attenuated collagen deposition and myofibroblast differentiation and expansion in the UUO model of kidney fibrosis. In addition to the ERK1/2 pathway trametinib also ameliorated mTORC1 activation, another key pro-fibrotic signalling pathway, in injured kidneys. Trametinib also supressed ERK1/2 and mTORC1 pathways activation in cultured primary human renal fibroblasts in response to TGF-β1. Additionally, trametinib reduced the expression of the myofibroblast marker αSMA and the proliferation of these cells.. Crucially, trametinib also significantly ameliorated renal fibrosis progression when administered to animals with established fibrotic injury.
Conclusion
Our work shows that trametinib could be beneficial for the treatment of chronic renal fibrotic diseases of diverse aetiologies.
Sirius red staining of kidney sections from UUO or contralateral control kidneys 7days afer surgery. Animals received trametinib (3mg/kg for 6days) or vehicle as indicated. N=6