title: Attenuation of renal fibrosis by proteasome inhibition in rat obstructive nephropathy: possible role of nuclear factor kappaB.
abstract: 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.
authors.affiliation: Department of Applied Pharmacology and Therapeutics, Osaka City University Medical School, Osaka 545-8585, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Tashiro
authors.forename: Satoshi
authors.initials: S
authors.lastname: Tamada
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Kuwabara
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Komiya
authors.forename: Kaori
authors.initials: K
authors.lastname: Takekida
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Asai
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Iwao
authors.forename: Kazunobu
authors.initials: K
authors.lastname: Sugimura
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Matsumura
authors.forename: Masanori
authors.initials: M
authors.lastname: Takaoka
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Nakatani
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Miura
mesh_terms: 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
chemical_list: 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