AXL targeting reduces fibrosis development in experimental unilateral ureteral obstruction

Show full item record



Permalink

http://hdl.handle.net/10138/304662

Citation

Landolt , L , Furriol , J , Babickova , J , Ahmed , L , Eikrem , O , Skogstrand , T , Scherer , A , Suliman , S , Leh , S , Lorens , J B , Gausdal , G , Marti , H P & Osman , T 2019 , ' AXL targeting reduces fibrosis development in experimental unilateral ureteral obstruction ' , Physiological Reports , vol. 7 , no. 10 , 14091 , pp. e14091 . https://doi.org/10.14814/phy2.14091

Title: AXL targeting reduces fibrosis development in experimental unilateral ureteral obstruction
Author: Landolt, Lea; Furriol, Jessica; Babickova, Janka; Ahmed, Lavina; Eikrem, Oystein; Skogstrand, Trude; Scherer, Andreas; Suliman, Salwa; Leh, Sabine; Lorens, J. B.; Gausdal, Gro; Marti, H.P.; Osman, Tarig
Contributor: University of Helsinki, Institute for Molecular Medicine Finland
Date: 2019-05
Language: eng
Number of pages: 20
Belongs to series: Physiological Reports
ISSN: 2051-817X
URI: http://hdl.handle.net/10138/304662
Abstract: 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 C57BL/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 (alpha SMA), as well as reduced mRNA abundance of key regulators of fibrosis such as transforming growth factor (Tgf beta), 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) EMT induction. Furthermore, less F4/80 positive cells, less activity of pathways related to the immune system and lower abundance of MCP1, MCP3, MCP5, 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.
Subject: 3111 Biomedicine
AXL targeting
Bemcentinib (BGB324)
renal fibrosis
UUO
CHRONIC KIDNEY-DISEASE
RECEPTOR TYROSINE KINASES
TO-MESENCHYMAL TRANSITION
RENAL FIBROSIS
MECHANISMS
INFLAMMATION
INHIBITION
COLLAGEN
MICE
ACCUMULATION
Rights:


Files in this item

Total number of downloads: Loading...

Files Size Format View
PHY2_7_e14091.pdf 10.36Mb PDF View/Open

This item appears in the following Collection(s)

Show full item record