Mice lacking the matrix metalloproteinase-9 gene reduce renal interstitial fibrosis in obstructive nephropathy.
Matrix metalloproteinase-9 (MMP-9) is one of the major components of the matrix proteolytic network, and its role in the pathogenesis of renal interstitial fibrosis remains largely unknown. Here, we demonstrate that ablation of MMP-9 attenuated renal interstitial fibrotic lesions in obstructive nephropathy. Mice lacking MMP-9 were less likely to develop morphological injury, which was characterized by a reduced disruption of tubular basement membrane (TBM) and expression of fibronectin as well as deposition of total tissue collagen in the kidneys after sustained ureteral obstruction compared with their wild-type counterparts. Deficiency of MMP-9 blocked tubular epithelial-to-myofibroblast transition (EMT) but did not alter the induction of transforming growth factor (TGF)-β1 axis expression in the obstructed kidneys. In vitro, TBM, which was digested by MMP-9 instead of MMP-9 itself, induces EMT and enhances migration of transformed cells. Thus increased MMP-9 is detrimental in renal interstitial fibrogenesis through a cascade of events that leads to TBM destruction and in turn to promotion of EMT. Our findings establish a crucial and definite importance of MMP-9 in the pathogenesis of renal interstitial fibrosis at the whole-animal level.
Wang
Xiaohua
X
Center of Kidney Disease, 2nd Affiliated Hospital, Nanjing Medical Univ., 262 Zhongshan East Rd., Nanjing 210003, Jiangsu Province, China.
Zhou
Yang
Y
Tan
Ruoyun
R
Xiong
Mingxia
M
He
Weichun
W
Fang
Li
L
Wen
Ping
P
Jiang
Lei
L
Yang
Junwei
J
D000199:Actins / Q000096:biosynthesis; D000818:Animals; D015153:Blotting, Western; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005355:Fibrosis; D007150:Immunohistochemistry; D007668:Kidney / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D009395:Nephritis, Interstitial / Q000209:etiology / Q000235:genetics* / Q000473:pathology*; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis; D014517:Ureteral Obstruction / Q000150:complications / Q000473:pathology*
C558396:Acta2 protein, mouse; D000199:Actins; D053773:Transforming Growth Factor beta1; D012313:RNA; D003094:Collagen; D020780:Matrix Metalloproteinase 9