We previously reported that
pyrrolidine dithiocarbamate blocked
nuclear factor-kappaB (
NF-kappaB) activation and attenuated interstitial
inflammation and tubulointerstitial
fibrosis in the rat obstructive nephropathy. Since
pyrrolidine dithiocarbamate is an
anti-oxidant and possesses additional biological properties, present experiment was conducted to clarify further the role of
NF-kappaB in the development of tubulointerstitial
fibrosis in obstructed kidney using a
proteasome inhibitor that blocks
NF-kappaB through stabilizing IkappaB, an endogenous inhibitor of
NF-kappaB. At 5 days following unilateral
ureteral obstruction (UUO) in rats, obstructed kidney exhibited tubulointerstitial
fibrosis that was associated with macrophage infiltration. UUO decreased renal cortical IkappaB
protein contents with concomitant increases in
NF-kappaB DNA-binding activity and gene expression of
monocyte chemoattractant protein-1. Administration of PSI, N-benzyloxy-carbonyl-Ile-Glu (O-t-Bu)-Ala-
leucinal, a
proteasome inhibitor, (3 mg/kg/day, s.c., b.i.d) to UUO rats inhibited
proteasome activity and attenuated the changes in IkappaB content,
NF-kappaB activity and MCP-1
mRNA expression observed in UUO rats. PSI also decreased macrophage influx and attenuated the development of
fibrosis. Furthermore, up-regulated gene expression of pro-fibrogenic molecules observed in the obstructed kidney was attenuated by PSI. These results further support the notion that
NF-kappaB plays an important role in the development of renal
fibrosis in the obstructive nephropathy.