TNF-alpha deficiency accelerates renal tubular interstitial fibrosis in the late stage of ureteral obstruction.
TNF-alpha and TGF-beta1 have a complementary relationship in fibrogenesis. This study was performed to investigate the role of TNF-alpha in renal tubular interstitial fibrosis. We compared the extent of renal tubular interstitial fibrosis after unilateral ureteral obstruction (UUO) between wild-type and TNF-alpha-deficient mice by using immunohistochemistry, enzyme-linked immunoassay, and the real-time polymerase chain reaction (PCR). In comparison with wild-type mice, there was no significant difference in the extent of renal fibrosis in the TNF-alpha-deficient mice at 2 weeks after UUO. By 4 weeks after UUO, however, fibrosis marked an increase in the TNF-alpha-deficient mice to exceed that in the wild-type mice. Immunohistochemistry, enzyme-linked immunoassay, and real-time PCR demonstrated an increase of extracellular matrix in the kidneys of TNF-alpha-deficient mice that was caused by upregulation of the expression of TGF-beta1 and Snail, which in turn resulted from an increase of infiltrating macrophages. Real-time PCR revealed an increase in expression of the TNF-alpha type 2 receptor at 4 weeks after UUO, which explained the difference in the extent of renal fibrosis between TNF-alpha-deficient and wild-type mice. In the chronic stage of renal fibrosis, TNF-alpha suppresses the infiltration of macrophages by inducing TNF-alpha type 2 receptor expression, resulting in the amelioration of fibrosis.
First Department of Pathology, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-0012, Japan.
Yoshifumi
Y
Morimoto
Zhibo
Z
Gai
Hiroyuki
H
Tanishima
Motohisa
M
Kawakatsu
Shunji
S
Itoh
Ikuji
I
Hatamura
Yasuteru
Y
Muragaki
D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D005355:Fibrosis; D005786:Gene Expression Regulation; D007150:Immunohistochemistry; D007684:Kidney Tubules / Q000378:metabolism / Q000473:pathology*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency* / Q000378:metabolism; D014517:Ureteral Obstruction / Q000150:complications* / Q000235:genetics / Q000473:pathology*
D000199:Actins; D024042:Collagen Type I; D012333:RNA, Messenger; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha