The role of the vitamin K-dependent growth factor Gas6 in glomerular pathophysiology

The product of growth arrest-specific gene 6 (gas6) is a unique vitamin K-dependent growth-potentiating factor for vascular smooth muscle cells, and anticoagulant warfarin inhibits the activation process of the protein. It has been reported that Gas6 is also a mitogen for mesangial cells, and that warfarin inhibits mesangial cell proliferation by blocking the activation of Gas6. A recent series of studies has revealed the in-vivo roles of Gas6 and its receptor Axl in the progression of various kidney diseases. This review summarizes these studies and discusses the possible interventions targeting the Gas6/Axl pathway to prevent the progression of kidney diseases.

The expression of Gas6 and Axl is upregulated in an acute model of glomerulonephritis in rats, and the interference of the Gas6/Axl pathway by warfarin or the extracellular domain of Axl inhibits the progression of diseases. Induction of chronic glomerulonephritis in Gas6 mice results in less mortality, proteinuria, and histological changes of kidneys compared to wild-type mice. Administration of recombinant Gas6 reverses these phenotypes. Expression of Gas6 is also upregulated in streptozotocin-induced diabetic nephropathy, and administration of low-dose warfarin decreases albuminuria and hypertrophy of glomeruli. Possible roles of Gas6 are also reported in renal allograft dysfunction of rats and humans.

The importance of the Gas6/Axl pathway has been implicated in many types of kidney disease. Further investigations on the role of the Gas6/Axl pathway in human kidney diseases and the development of specific antagonists targeting the pathway are warranted.