Advanced Glycation Endprocucts Is Involved in the Development of Age-Associated Glomeruloselerosis through Growth Arrest Specific Gene 6.

Advanced glycation end products (AGEs) contribute to kidney disease due to diabetes or aging by stimulating glomerular mesangial cells, which promote the expression of various growth factors. Further, aging is characterized by renal structural abnormalities, such as glomerulosclerosis, resembling those observed in diabetes. However, the relationship between AGEs, growth factors, and kidney lesions remains largely uncharacterized. We have reported that growth arrest-specific gene 6 (Gas6), a new mitogen for mesangial cells, plays a key role for the development of diabetic nephropathy. In this study, we examine whether the link between AGEs and Gas6 is involved in the development of age-associated glomerular lesions. First, to examine the relationship between AGEs, Gas6 and aging, the isolation of glomeruli was performed from young (1 month) and aged (12months) mice, and the expression of Gas6 in isolated glomeruli was quantified by real-time PCR. Renal accumulation of AGEs (carboxyethyl-lysine) was also quantified by dot blot assay of kidney lysates. Glomerular expression of Gas6 was increased by 2 folds in aged mice. Renal AGE accumulation was also increased with age. Next, Gas6 knock out (KO) and wild type (WT) mice were studied at 3, 12, and 24 months (n=6 animals/group). Glomerular surface area and mesangial area were also progressively increased in WT mice with age by morphometric analyses. However, in KO mice, the increase of glomerular surface area was suppressed at 12months, and mesangial expansion was significantly ameliorated at 24 months compared with age-matched WT mice, whereas there is no difference in the levels of renal AGEs between age-matched WT and KO mice. Further, to find a link between AGEs and Gas6, we examined whether AGEs induce Gas6 in mesangial cells and checked the transcriptional activity of type IV collagen (Co14), which is the major component of extracellular matrix in glomemlosclerosis, under AGE stimulation in mesangial cells both from WT and KO mice. AGEs induced Gas6 in mesangial cells from WT mice. AGEs increased the transcriptional activity of Co14 in mesangial cells from WT mice, which is significantly suppressed in those from KO mice. These results suggest that Gas6 is involved in the development of age-associated glomerular damages via AGE accumulation, and that Gas6 could be a novel therapeutic target for aging kidney. [ABSTRACT FROM AUTHOR]