Abstract
BackgroundGas6 is a growth factor that causes proliferation of mesangial cells in the development of glomerulonephritis. Gas6 can bind to three kinds of receptors; Axl, Dtk, and Mer. However, their expression and functions are not entirely clear in the different glomerular cell types. Meanwhile, representative cell cycle regulatory protein p27 has been reported to be expressed in podocytes in normal glomeruli with decreased expression in proliferating glomeruli, which inversely correlated with mesangial proliferation in human IgA nephropathy (IgAN).MethodsThe aim of this study is to clarify Gas6 involvement in the progression of IgAN. Expression of Gas6/Axl/Dtk was examined in 31 biopsy proven IgAN cases. We compared the expression levels with histological severity or clinical data. Moreover, we investigated the expression of Gas6 and its receptors in cultured podocytes.ResultsIn 28 of 31 cases, Gas6 was upregulated mainly in podocytes. In the other 3 cases, Gas6 expression was induced in endothelial and mesangial cells, which was similar to animal nephritis models. Among 28 podocyte type cases, the expression level of Gas6 correlated with the mesangial hypercellularity score of IgAN Oxford classification and urine protein excretion. It also inversely correlated with p27 expression in glomeruli. As for the receptors, Axl was mainly expressed in endothelial and mesangial cells, while Dtk was expressed in podocytes. In vitro, Dtk was expressed in cultured murine podocytes, and the expression of p27 was decreased by Gas6 stimulation.ConclusionsGas6 was uniquely upregulated in either endothelial/mesangial cells or podocytes in IgAN. The expression pattern can be used as a marker to classify IgAN. Gas6 has a possibility to be involved in not only mesangial proliferation via Axl, but also podocyte injury via Dtk in IgAN.
Highlights
Gas6 is a growth factor which is post-translationally modified with c- carboxylation of glutamate residues at its N terminus in the presence of vitamin K and inhibited by warfarin, an optional therapy for human kidney diseases
We investigated whether expression of Gas6 and its receptors is involved in the progression of IgA nephropathy (IgAN) through analysis of the relationship between Gas6 expression and clinicopathological characteristics
IgAN was Divided into Two Subgroups According to Gas6 Expression Pattern
Summary
Gas is a growth factor which is post-translationally modified with c- carboxylation of glutamate residues at its N terminus in the presence of vitamin K and inhibited by warfarin, an optional therapy for human kidney diseases. Gas is expressed in the mesangial area in animal kidney disease models, such as rat antiThy-1 nephritis [1], anti-GBM nephritis [2] and streptozotocin induced diabetic rat and mouse model [3]. Gas can bind to three kinds of receptors; Axl, Dtk ( called as Tyro or Sky), and Mer. Among them, Axl has the highest binding affinity with Gas and is expressed in endothelial and mesangial cells in animal kidney disease models [4,5]. To our knowledge, no one has examined what kind of cell type expresses Dtk in glomeruli. Gas can bind to three kinds of receptors; Axl, Dtk, and Mer. Gas can bind to three kinds of receptors; Axl, Dtk, and Mer Their expression and functions are not entirely clear in the different glomerular cell types. Representative cell cycle regulatory protein p27 has been reported to be expressed in podocytes in normal glomeruli with decreased expression in proliferating glomeruli, which inversely correlated with mesangial proliferation in human IgA nephropathy (IgAN)
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