Open AccessAXL targeting reduces fibrosis development in experimental unilateral ureteral obstruction
Author(s) -
Landolt Lea,
Furriol Jessica,
Babickova Janka,
Ahmed Lavina,
Eikrem Øystein,
Skogstrand Trude,
Scherer Andreas,
Suliman Salwa,
Leh Sabine,
Lorens James B.,
Gausdal Gro,
Marti HansPeter,
Osman Tarig
Publication year - 2019
Publication title -
physiological reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.918
H-Index - 39
ISSN - 2051-817X
DOI - 10.14814/phy2.14091
Subject(s) - sirius red , fibrosis , kidney , myofibroblast , vimentin , medicine , cancer research , hydroxyproline , pathology , epithelial–mesenchymal transition , immunohistochemistry , cancer , metastasis
The AXL receptor tyrosine kinase ( RTK ) is involved in partial epithelial‐to‐mesenchymal transition ( EMT ) and inflammation – both main promoters of renal fibrosis development. The study aim was to investigate the role of AXL inhibition in kidney fibrosis due to unilateral ureteral obstruction ( UUO ). Eight weeks old male C57 BL /6 mice underwent UUO and were treated with oral AXL inhibitor bemcentinib ( n = 22), Angiotensin‐converting enzyme inhibitor ( ACEI , n = 10), ACEI and bemcentinib ( n = 10) or vehicle alone ( n = 22). Mice were sacrificed after 7 or 15 days and kidney tissues were analyzed by immunohistochemistry ( IHC ), western blot, ELISA , Sirius Red ( SR ) staining, and hydroxyproline (Hyp) quantification. RNA was extracted from frozen kidney tissues and sequenced on an Illumina HiSeq4000 platform. After 15 days the ligated bemcentinib‐treated kidneys showed less fibrosis compared to the ligated vehicle‐treated kidneys in SR analyses and Hyp quantification. Reduced IHC staining for Vimentin ( VIM ) and alpha smooth muscle actin ( α SMA ), as well as reduced mRNA abundance of key regulators of fibrosis such as transforming growth factor ( Tgfβ ), matrix metalloproteinase 2 ( Mmp2 ), Smad2 , Smad4 , myofibroblast activation ( Aldh1a2 , Crlf1 ), and EMT ( Snai1,2, Twist ), in ligated bemcentinib‐treated kidneys was compatible with reduced (partial) E MT induction. Furthermore, less F4/80 positive cells, less activity of pathways related to the immune system and lower abundance of MCP 1, MCP 3, MCP 5, and TARC in ligated bemcentinib‐treated kidneys was compatible with reduction in inflammatory infiltrates by bemcentinib treatment. The AXL RTK pathway represents a promising target for pharmacologic therapy of kidney fibrosis.