title: Axl tyrosine kinase protects against tubulo-interstitial apoptosis and progression of renal failure in a murine model of chronic kidney disease and hyperphosphataemia.
abstract: Chronic kidney disease (CKD) is defined as the progressive loss of renal function often involving glomerular, tubulo-interstitial and vascular pathology. CKD is associated with vascular calcification; the extent of which predicts morbidity and mortality. However, the molecular regulation of these events and the progression of chronic kidney disease are not fully elucidated. To investigate the function of Axl receptor tyrosine kinase in CKD we performed a sub-total nephrectomy and fed high phosphate (1%) diet to Axl+/+ and Axl-/- mice. Plasma Gas6 (Axl' ligand), renal Axl expression and downstream Akt signalling were all significantly up-regulated in Axl+/+ mice following renal mass reduction and high phosphate diet, compared to age-matched controls. Axl-/- mice had significantly enhanced uraemia, reduced bodyweight and significantly reduced survival following sub-total nephrectomy and high phosphate diet compared to Axl+/+ mice; only 45% of Axl-/- mice survived to 14 weeks post-surgery compared to 87% of Axl+/+ mice. Histological analysis of kidney remnants revealed no effect of loss of Axl on glomerular hypertrophy, calcification or renal sclerosis but identified significantly increased tubulo-interstitial apoptosis in Axl-/- mice. Vascular calcification was not induced in Axl+/+ or Axl-/- mice in the time frame we were able to examine. In conclusion, we identify the up-regulation of Gas6/Axl signalling as a protective mechanism which reduces tubulo-interstitial apoptosis and slows progression to end-stage renal failure in the murine nephrectomy and high phosphate diet model of CKD.
authors.affiliation: Institute of Cardiovascular Sciences, Faculty of Medical and Human Sciences, University of Manchester, Manchester, United Kingdom; Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Manchester, United Kingdom.
authors.forename: Gareth D
authors.initials: GD
authors.lastname: Hyde
authors.affiliation: Institute of Cardiovascular Sciences, Faculty of Medical and Human Sciences, University of Manchester, Manchester, United Kingdom; Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Manchester, United Kingdom.
authors.forename: Rebecca F
authors.initials: RF
authors.lastname: Taylor
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.
authors.forename: Nick
authors.initials: N
authors.lastname: Ashton
authors.affiliation: Institute of Cardiovascular Sciences, Faculty of Medical and Human Sciences, University of Manchester, Manchester, United Kingdom.
authors.forename: Samantha J
authors.initials: SJ
authors.lastname: Borland
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.
authors.forename: Hon Sing Geoffrey
authors.initials: HS
authors.lastname: Wu
authors.affiliation: Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Manchester, United Kingdom; Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Gilmore
authors.affiliation: Institute of Cardiovascular Sciences, Faculty of Medical and Human Sciences, University of Manchester, Manchester, United Kingdom; Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Manchester, United Kingdom.
authors.forename: Ann E
authors.initials: AE
authors.lastname: Canfield
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D017931:DNA Primers / Q000235:genetics; D005786:Gene Expression Regulation / Q000502:physiology*; D054559:Hyperphosphatemia / Q000201:enzymology / Q000503:physiopathology*; D020287:In Situ Nick-End Labeling; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood; D007668:Kidney / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009392:Nephrectomy; D010710:Phosphates / Q000008:administration & dosage; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D051436:Renal Insufficiency, Chronic / Q000201:enzymology / Q000503:physiopathology*; D015398:Signal Transduction / Q000502:physiology; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D017931:DNA Primers; D036341:Intercellular Signaling Peptides and Proteins; D010710:Phosphates; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6; C000722290:AXL receptor tyrosine kinase, mouse