Halofuginone prevents extracellular matrix deposition in diabetic nephropathy.
Transforming growth factor-beta (TGF-beta) is known to promote the accumulation of extracellular matrix (ECM) and the development of diabetic nephropathy. Halofuginone, an analog of febrifugine, has been shown to block TGF-beta(1) signaling and subsequent type I collagen production. Here, the inhibitory effect of halofuginone on diabetic nephropathy was examined. Halofuginone suppressed Smad2 phosphorylation induced by TGF-beta(1) in cultured mesangial cells. In addition, the expression of TGF-beta type 2 receptor decreased by halofuginone. Halofuginone showed an inhibitory effect on type I collagen and fibronectin expression promoted by TGF-beta(1). An in vivo experiment using db/db mice confirmed the ability of halofuginone to suppress mesangial expansion and fibronectin overexpression in the kidneys. Moreover, an analysis of urinary 8-OHdG level and dihydroethidium fluorescence revealed that halofuginone reduced oxidative stress in the glomerulus of db/db mice. These data indicate that halofuginone prevents ECM deposition and decreases oxidative stress, thereby suppressing the progression of diabetic nephropathy.
Sato
Seiya
S
Department of Clinical Cell Biology and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
Kawamura
Harukiyo
H
Takemoto
Minoru
M
Maezawa
Yoshiro
Y
Fujimoto
Masaki
M
Shimoyama
Tatsushi
T
Koshizaka
Masaya
M
Tsurutani
Yuya
Y
Watanabe
Aki
A
Ueda
Shiro
S
Halevi
Karin
K
Saito
Yasushi
Y
Yokote
Koutaro
K
D000818:Animals; D024042:Collagen Type I / Q000037:antagonists & inhibitors / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000473:pathology*; D005109:Extracellular Matrix / Q000187:drug effects* / Q000473:pathology*; D005353:Fibronectins / Q000037:antagonists & inhibitors / Q000378:metabolism; D050527:Mesangial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D018384:Oxidative Stress / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology*; D052999:Quinazolinones / Q000494:pharmacology*; D051381:Rats; D051899:Smad2 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors
D024042:Collagen Type I; D005353:Fibronectins; D010880:Piperidines; D052999:Quinazolinones; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta; C010176:halofuginone