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Basic Research
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The MEK Inhibitor Trametinib Ameliorates Kidney Fibrosis by Suppressing ERK1/2 and mTORC1 Signaling

Petros Andrikopoulos, Julius Kieswich, Sabrina Pacheco, Luxme Nadarajah, Steven Michael Harwood, Caroline E. O'Riordan, Christoph Thiemermann and Muhammad M. Yaqoob
JASN January 2019, 30 (1) 33-49; DOI: https://doi.org/10.1681/ASN.2018020209
Petros Andrikopoulos
Diabetic Kidney Disease Centre, Renal Unit, Barts Health National Health Service Trust, The Royal London Hospital, London, UK; andCentre for Translational Medicine and Therapeutics, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
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Julius Kieswich
Diabetic Kidney Disease Centre, Renal Unit, Barts Health National Health Service Trust, The Royal London Hospital, London, UK; andCentre for Translational Medicine and Therapeutics, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
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Sabrina Pacheco
Diabetic Kidney Disease Centre, Renal Unit, Barts Health National Health Service Trust, The Royal London Hospital, London, UK; andCentre for Translational Medicine and Therapeutics, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
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Luxme Nadarajah
Centre for Translational Medicine and Therapeutics, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
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Steven Michael Harwood
Diabetic Kidney Disease Centre, Renal Unit, Barts Health National Health Service Trust, The Royal London Hospital, London, UK; andCentre for Translational Medicine and Therapeutics, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
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Caroline E. O'Riordan
Centre for Translational Medicine and Therapeutics, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
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Christoph Thiemermann
Diabetic Kidney Disease Centre, Renal Unit, Barts Health National Health Service Trust, The Royal London Hospital, London, UK; andCentre for Translational Medicine and Therapeutics, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
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Muhammad M. Yaqoob
Diabetic Kidney Disease Centre, Renal Unit, Barts Health National Health Service Trust, The Royal London Hospital, London, UK; andCentre for Translational Medicine and Therapeutics, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
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Abstract

Background During kidney fibrosis, a hallmark and promoter of CKD (regardless of the underlying renal disorder leading to CKD), the extracellular-regulated kinase 1/2 (ERK1/2) pathway, is activated and has been implicated in the detrimental differentiation and expansion of kidney fibroblasts. An ERK1/2 pathway inhibitor, trametinib, is currently used in the treatment of melanoma, but its efficacy in the setting of CKD and renal fibrosis has not been explored.

Methods We investigated whether trametinib has antifibrotic effects in two mouse models of renal fibrosis—mice subjected to unilateral ureteral obstruction (UUO) or fed an adenine-rich diet—as well as in cultured primary human fibroblasts. We also used immunoblot analysis, immunohistochemical staining, and other tools to study underlying molecular mechanisms for antifibrotic effects.

Results Trametinib significantly attenuated collagen deposition and myofibroblast differentiation and expansion in UUO and adenine-fed mice. We also discovered that in injured kidneys, inhibition of the ERK1/2 pathway by trametinib ameliorated mammalian target of rapamycin complex 1 (mTORC1) activation, another key profibrotic signaling pathway. Trametinib also inhibited the ERK1/2 pathway in cultured primary human renal fibroblasts stimulated by application of TGF-β1, the major profibrotic cytokine, thereby suppressing downstream mTORC1 pathway activation. Additionally, trametinib reduced the expression of myofibroblast marker α-smooth muscle actin and the proliferation of renal fibroblasts, corroborating our in vivo data. Crucially, trametinib also significantly ameliorated renal fibrosis progression when administered to animals subsequent to myofibroblast activation.

Conclusions Further study of trametinib as a potential candidate for the treatment of chronic renal fibrotic diseases of diverse etiologies is warranted.

  • renal fibrosis
  • ERK1/2
  • mTORC1
  • Trametinib
  • UUO
  • chronic kidney disease
  • Copyright © 2019 by the American Society of Nephrology
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Journal of the American Society of Nephrology: 30 (1)
Journal of the American Society of Nephrology
Vol. 30, Issue 1
January 2019
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The MEK Inhibitor Trametinib Ameliorates Kidney Fibrosis by Suppressing ERK1/2 and mTORC1 Signaling
Petros Andrikopoulos, Julius Kieswich, Sabrina Pacheco, Luxme Nadarajah, Steven Michael Harwood, Caroline E. O'Riordan, Christoph Thiemermann, Muhammad M. Yaqoob
JASN Jan 2019, 30 (1) 33-49; DOI: 10.1681/ASN.2018020209

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The MEK Inhibitor Trametinib Ameliorates Kidney Fibrosis by Suppressing ERK1/2 and mTORC1 Signaling
Petros Andrikopoulos, Julius Kieswich, Sabrina Pacheco, Luxme Nadarajah, Steven Michael Harwood, Caroline E. O'Riordan, Christoph Thiemermann, Muhammad M. Yaqoob
JASN Jan 2019, 30 (1) 33-49; DOI: 10.1681/ASN.2018020209
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Keywords

  • renal fibrosis
  • ERK1/2
  • mTORC1
  • Trametinib
  • UUO
  • chronic kidney disease

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