Inhibition of tyrosine kinase receptor signaling attenuates fibrogenesis in an ex vivo model of human renal fibrosis

Emilia Bigaeva, Elisabeth G. D. Stribos, Henricus A. M. Mutsaers, Bram Piersma, Anna M. Leliveld, Igle J. de Jong, Ruud A. Bank, Marc A. Seelen, Harry van Goor, Lutz Wollin, Peter Olinga*, Miriam Boersema

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

3 Citations (Scopus)
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Abstract

Poor translation from animal studies to human clinical trials is one of the main hurdles in the development of new drugs. Here, we used precision-cut kidney slices (PCKS) as a translational model to study renal fibrosis and to investigate whether inhibition of tyrosine kinase receptors, with the selective inhibitor nintedanib, can halt fibrosis in murine and human PCKS. We used renal tissue of murine and human origins to obtain PCKS. Control slices and slices treated with nintedanib were studied to assess viability, activation of tyrosine kinase receptors, cell proliferation, collagen type I accumulation, and gene and protein regulation. During culture, PCKS spontaneously develop a fibrotic response that resembles in vivo fibrogenesis. Nintedanib blocked culture-induced phosphorylation of platelet-derived growth factor receptor and vascular endothelial growth factor receptor. Furthermore, nintedanib inhibited cell proliferation and reduced collagen type I accumulation and expression of fibrosis-related genes in healthy murine and human PCKS. Modulation of extracellular matrix homeostasis was achieved already at 0.1 μM, whereas high concentrations (1 and 5 μM) elicited possible nonselective effects. In PCKS from human diseased renal tissue, nintedanib showed limited capacity to reverse established fibrosis. In conclusion, nintedanib attenuated the onset of fibrosis in both murine and human PCKS by inhibiting the phosphorylation of tyrosine kinase receptors; however, the reversal of established fibrosis was not achieved.

Original languageEnglish
Pages (from-to)F117-F134
Number of pages18
JournalAmerican journal of physiology-Renal physiology
Volume318
Issue number1
Early online date18-Nov-2019
DOIs
Publication statusPublished - Jan-2020

Keywords

  • nintedanib
  • precision-cut kidney slices
  • renal fibrosis
  • tyrosine kinase receptor
  • CUT KIDNEY SLICES
  • GROWTH-FACTOR
  • ANGIOKINASE INHIBITOR
  • LIVER SLICES
  • CELL CANCER
  • EARLY-ONSET
  • BIBF 1120
  • NINTEDANIB
  • EXPRESSION
  • ANGIOGENESIS

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