Renal expression of proto-oncogene Ets-1 on matrix remodeling in experimental diabetic nephropathy

The molecular mechanisms of glomerulosclerosis and tubulointerstitial fibrosis in diabetic nephropathy (DN) have received scant attention. Ets-1 proto-oncogene plays a role in matrix remodeling by regulating matrix-degrading enzymes. We investigated the possible role of Ets-1 in the pathogenesis of DN. 6-week-old male Sprague-Dawley rats were divided into two experimental groups as follows: control group (n=30) and a Diabetes mellitus group (n=40) induced by injection of streptozotozin (STZ). The rats were investigated at 1, 4, 8, 12 and 16 weeks after STZ-treatment. By means of immunohistochemistry, the expression of Ets-1 in glomeruli was significantly increased in STZ-treated rat kidneys from week 1 (P<0.05) and reached the peak at week 4 (P<0.05), followed by a downward trend at subsequent time points. Similarly, the expression of Ets-1 in the tubulointerstitium was also markedly increased from week 1 (P<0.05) and reached a maximum at week 8 (P<0.05). By double immunostaining, Ets-1-positive cells were frequently found to co-express matrix metalloproteinase-2 (MMP-2) in STZ-treated rat kidneys. Increased expression of tissue inhibitor of metalloproteinase-2 (TIMP-2) coincided with increased expression of α-smooth muscle actin (α-SMA) in STZ-induced DN. A positive relationship was observed between the expression of Ets-1 in glomeruli or tubulointerstitium and the expression of MMP-2 (P<0.01; P<0.01, respectively) in STZ-treated rat kidneys. The ratio of MMP-2 and TIMP-2 in glomeruli or tubulointerstitium was negatively correlated with deposition of type IV collagen (P<0.01; P<0.01, respectively). These findings suggest that Ets-1 may play a critical role in fine-tuning matrix remodeling of STZ-induced DN.