Attenuation of renal fibrosis by proteasome inhibition in rat obstructive nephropathy: possible role of nuclear factor kappaB.
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.
Tashiro
Koichiro
K
Department of Applied Pharmacology and Therapeutics, Osaka City University Medical School, Osaka 545-8585, Japan.
Tamada
Satoshi
S
Kuwabara
Nobuyuki
N
Komiya
Toshiyuki
T
Takekida
Kaori
K
Asai
Toshihiro
T
Iwao
Hiroshi
H
Sugimura
Kazunobu
K
Matsumura
Yasuo
Y
Takaoka
Masanori
M
Nakatani
Tatsuya
T
Miura
Katsuyuki
K
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000378:metabolism; D003546:Cysteine Endopeptidases; D003593:Cytoplasm / Q000378:metabolism; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D005355:Fibrosis; D020672:I-kappa B Proteins / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000473:pathology*; D007672:Kidney Cortex / Q000473:pathology; D008264:Macrophages / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology*; D046988:Proteasome Endopeptidase Complex; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D013997:Time Factors; D015854:Up-Regulation
D018932:Chemokine CCL2; D020672:I-kappa B Proteins; D009097:Multienzyme Complexes; D016328:NF-kappa B; D012333:RNA, Messenger; D004247:DNA; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex