Axl tyrosine kinase protects against tubulo-interstitial apoptosis and progression of renal failure in a murine model of chronic kidney disease and hyperphosphataemia.

Gareth D Hyde,Rebecca F Taylor,Ann E Canfield,Andrew P Gilmore,Hon Sing Geoffrey Wu,Nick Ashton,Samantha J Borland

doi:10.1371/journal.pone.0102096

Gareth D Hyde, Rebecca F Taylor + Show 5 more

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https://doi.org/10.1371/journal.pone.0102096

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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.

Highlights

Chronic kidney disease (CKD) is a major healthcare burden and significant cause of death worldwide
We show that sub-total nephrectomy and high phosphate diet induced glomerular hypertrophy; no significant difference between Axl+/+ and Axl2/2 mice was seen (Figure S2)
In this study we investigated the role of Axl tyrosine kinase in the murine sub-total nephrectomy and high phosphate diet model of CKD and vascular calcification (VC)

Summary

Introduction

Chronic kidney disease (CKD) is a major healthcare burden and significant cause of death worldwide. CKD can be initiated by several different insults, it is believed to converge on common progressive pathways leading to loss of renal function and end-stage renal failure [1]. Cardiovascular disease accounts for a significant proportion of mortality within CKD patients. Vascular calcification (VC) is detected in over 80% of end-stage renal disease patients and its extent associates with increased morbidity and mortality [2,3,4]. Axl is a member of the TAM (Tyro, Axl and Mertk) family of receptor tyrosine kinases which are all activated by the ligand Gas. Binding of Gas to Axl leads to receptor dimerisation, autophosphorylation and activation of downstream signalling pathways including PI3-Kinase/Akt and Erk1/2 resulting in pro-survival and proliferative responses, respectively [5,6]

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