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.
Liu
Dian-xin
DX
Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Nangang District, Heilongjiang Province, China.
Liu
Xiao-min
XM
Su
Ying
Y
Zhang
Xiao-juan
XJ
D000199:Actins / Q000378:metabolism; D000818:Animals; D024141:Collagen Type IV / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D003928:Diabetic Nephropathies / Q000378:metabolism / Q000473:pathology*; D005355:Fibrosis; D050533:Glomerular Basement Membrane / Q000378:metabolism / Q000473:pathology; D005920:Glomerular Mesangium / Q000378:metabolism / Q000473:pathology; D007668:Kidney / Q000378:metabolism / Q000473:pathology*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D050784:Proto-Oncogene Protein c-ets-1 / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013311:Streptozocin; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism
D000199:Actins; D024141:Collagen Type IV; D020778:Matrix Metalloproteinase 2; D050784:Proto-Oncogene Protein c-ets-1; D013311:Streptozocin; D019716:Tissue Inhibitor of Metalloproteinase-2; C494043:Ets1 protein, rat; C498862:Acta2 protein, rat; C522363:Mmp2 protein, rat