Molecular mechanisms and therapeutic strategies of chronic renal injury: the role of nuclear factor kappaB activation in the development of renal fibrosis.
Tubulointerstitial fibrosis is a common feature of many progressive renal diseases and is a main determinant that leads to an irreversible loss of renal function. In chronic cyclosporin A nephrotoxicity, we previously reported that inflammatory responses such as macrophage infiltration preceded interstitial fibrosis. This inflammation was accompanied by an elevation in renal nuclear factor kappaB (NF-kappaB) activity. Similar findings were obtained in chronic tacrolimus nephrotoxicity and obstructive nephropathy. Inhibition of NF-kappaB markedly attenuated renal inflammation and interstitial fibrosis in these models. Furthermore, administration of oral adsorbent (Kremezin) significantly attenuated the increase in renal NF-kappaB activity and concomitantly reduced interstitial inflammation and renal fibrosis in chronic renal failure rats. Elimination of indoxyl sulfate by this adsorbent is likely involved in this mechanism since it is known that indoxyl sulfate activates NF-kappaB in renal tubular cells. It is suggested that strategy aiming at NF-kappaB inhibition is important to prevent the progression of renal fibrosis.
Tamada
Satoshi
S
Department of Urology, Osaka City University Medical School, Osaka, Japan. s-tamada@msic.med.osaka-cu.ac.jp
Asai
Toshihiro
T
Kuwabara
Nobuyuki
N
Iwai
Tomoaki
T
Uchida
Junji
J
Teramoto
Kae
K
Kaneda
Noriko
N
Yukimura
Tokihito
T
Komiya
Toshiyuki
T
Nakatani
Tatsuya
T
Miura
Katsuyuki
K
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002244:Carbon / Q000494:pharmacology; D004195:Disease Models, Animal; D005355:Fibrosis; D007249:Inflammation / Q000378:metabolism / Q000517:prevention & control; D007674:Kidney Diseases / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010087:Oxides / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D012084:Renin-Angiotensin System / Q000187:drug effects; D013859:Thiocarbamates / Q000494:pharmacology
D047228:Angiotensin II Type 1 Receptor Blockers; D000893:Anti-Inflammatory Agents; D016328:NF-kappa B; D010087:Oxides; D011759:Pyrrolidines; D013859:Thiocarbamates; C020972:pyrrolidine dithiocarbamic acid; D002244:Carbon; C040896:AST 120