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.

Role of Receptor Tyrosine Kinase Signaling in Renal Fibrosis

“…Gas6/Axl signaling regulates various cellular functions, such as survival, proliferation, adhesion, migration, blood clot stabilization, and inflammatory cytokine release [ 102 ]. Within the kidney, Axl and Gas6 are expressed in VSMCs, glomerular mesangial cells and tubular cells [ 103 ].…”

“…The basal expression of Gas6/Axl is low in normal kidney. However, its expression can be upregulated in several murine models of CKD including: glomerulonephritis induced by Thy1.1 antibody, nephrotoxic nephritis (NS), STZ-induced DN and a podocyte ablation model of glomerular albuminuria [ 103 ]. Patients with CKD had elevated plasma Gas6 levels [ 104 ].…”

Loss of PKCα increases arterial medial calcification in a uremic mouse model of chronic kidney disease

“…To determine the role of PKCα in uremia-induced arterial medial calcification, we used the two-stage subtotal nephrectomy and high phosphate diet model [24][25][26] . Female mice were used as our pilot studies showed that they were more resistant to acute renal failure following the uni-nephrectomy in the second surgical procedure compared with males (results not shown).…”

“…Therefore, this study aimed to determine whether loss of PKCα affects uremia-induced arterial medial calcification in vivo using the murine sub-total nephrectomy and high phosphate diet model [24][25][26] . Using novel X-ray micro computed tomography (µCT) approaches, we demonstrate that uremia-induced arterial medial calcification is increased significantly in PKCα -/mice compared to wild-type controls.…”

Proteomic Analysis of Urine from California Sea Lions (Zalophus californianus): a Resource for Urinary Biomarker Discovery

“…GAS6/AXL is known to reduce tubulo-interstitial apoptosis in chronic kidney injury models 43 and upregulation of this axis promotes glomerular hypertrophy in diabetic mice 44 . AXL expression is primarily located in vascular endothelia and the proximal tubule 45 .…”