Reversal of renal fibrosis, inflammation, and glomerular hypertrophy by kallikrein gene delivery.
Evidence suggests that the progression of renal fibrosis is a reversible process. Because inflammation plays a crucial role in the development of renal injury, we examined the effect of kallikrein and activation of the kinin B2 receptor on the reversal of salt-induced inflammation and renal fibrosis in Dahl salt-sensitive (DSS) rats. Four weeks after high salt loading, when renal injury was apparent, adenovirus harboring the human tissue kallikrein gene was injected into DSS rats. To determine the role of the B2 receptor in mediating the actions of kallikrein, icatibant, a kinin B2 receptor antagonist, was infused with kallikrein gene delivery. Two weeks after adenovirus injection, salt-induced glomerular sclerosis, tubular protein cast formation, and monocyte/ macrophage accumulation in the kidney were notably reversed by kallikrein. Decreased intercellular adhesion molecule-1 expression paralleled this observation. Kallikrein gene delivery also dramatically reduced collagens I, III, and IV and reticulin deposition, accompanied by a decline in myofibroblast accumulation and transforming growth factor-beta(1) expression. Moreover, kallikrein reversed salt-induced glomerular hypertrophy and inhibited the increase in levels of the cell cycle-inhibitory proteins p21 and p27. These protective actions of kallikrein were abolished by icatibant, indicating a B2 receptor-mediated event. In addition, kallikrein protected against salt-induced renal injury by diminishing urinary protein and blood urea nitrogen levels. Furthermore, kallikrein gene delivery restored nitric oxide production and suppressed NADH oxidase activity and superoxide generation. These results indicate that tissue kallikrein, through the kinin B2 receptor, reverses salt-induced inflammation, renal fibrosis, and glomerular hypertrophy via suppression of oxidative stress.
Bledsoe
Grant
G
Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, 29425, USA.
Shen
Bo
B
Yao
Yuyu
Y
Zhang
Jenny J
JJ
Chao
Lee
L
Chao
Julie
J
D000199:Actins; D000818:Animals; D001806:Blood Urea Nitrogen; D003094:Collagen / Q000378:metabolism; D005355:Fibrosis / Q000628:therapy*; D015316:Genetic Therapy; D006984:Hypertrophy / Q000628:therapy*; D007249:Inflammation / Q000628:therapy*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007668:Kidney / Q000473:pathology*; D007678:Kidney Glomerulus / Q000473:pathology*; D008297:Male; D009097:Multienzyme Complexes / Q000652:urine; D032390:Myoblasts, Smooth Muscle / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000652:urine; D018384:Oxidative Stress; D011507:Proteinuria / Q000209:etiology; D051381:Rats; D020303:Rats, Inbred Dahl; D012155:Reticulin / Q000378:metabolism; D020840:Tissue Kallikreins / Q000097:blood / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000378:metabolism
D000199:Actins; D003094:Collagen; D018799:Intercellular Adhesion Molecule-1; D009097:Multienzyme Complexes; D009247:NADH, NADPH Oxidoreductases; D012155:Reticulin; D020840:Tissue Kallikreins; D016212:Transforming Growth Factor beta; C498862:Acta2 protein, rat; C023107:NADH oxidase