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.