Expression of transforming growth factor-beta-inducible gene-h3 in normal and cyclosporine-treated rat kidney.
Up-regulation of transforming growth factor-beta (TGF-beta) is known to play an important role in the tubulointerstitial injury of chronic cyclosporin A (CsA) nephropathy, but the expression of the TGF-beta-inducible gene-h3 (betaig-h3) is undetermined. In this study we examined betaig-h3 expression and its relationship to tubulointerstitial injury in a rat model of chronic CsA nephropathy. Sprague-Dawley rats kept on a low-salt diet (0.05% sodium) were treated daily for 4 weeks with subcutaneous injections of vehicle (olive oil, 1 mL/kg) or CsA (15 mg/kg). The expression of betaig-h3 messenger RNA (mRNA) and protein was evaluated with the use of in situ hybridization, immunohistochemical methods, and immunoblotting. We also compared renal function, histologic findings (tubulointerstitial fibrosis), and expression of TGF-beta1 among treatment groups. In vehicle-treated kidney, betaig-h3 mRNA and protein were constitutively expressed in the outer medulla and cortex, which was confined to the terminal portion of afferent arterioles, the S3 segment of the proximal tubules, and distal convoluted tubules. CsA treatment significantly up-regulated betaig-h3 expression in the interstitium, especially in expanded and fibrotic areas. Quantitative analysis revealed that CsA induced a significant (twofold) increase in betaig-h3 mRNA and protein, and this increase was correlated with up-regulation of TGF-beta1 expression (r =.943, P <.001) and the tubulointerstitial fibrosis score (r =.746, P =.05). Our observations indicate that an increase in betaig-h3 expression, along with TGF-beta1 up-regulation, is closely associated with tubulointerstitial fibrosis in a rat model of chronic CsA nephropathy.
Department of Internal Medicine, Cell Death Disease Research Center, Catholic University of Korea, Seoul, South Korea.
Bo Kyung
BK
Sun
Can
C
Li
Sun Woo
SW
Lim
Ju Young
JY
Jung
Suk Hee
SH
Lee
In San
IS
Kim
Yong Soo
YS
Kim
Jin
J
Kim
Byung Kee
BK
Bang
Chul Woo
CW
Yang
D000818:Animals; D016572:Cyclosporine / Q000633:toxicity*; D016326:Extracellular Matrix Proteins / Q000187:drug effects / Q000235:genetics*; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000633:toxicity; D017403:In Situ Hybridization; D007668:Kidney / Q000187:drug effects / Q000473:pathology*; D008297:Male; D009395:Nephritis, Interstitial / Q000139:chemically induced / Q000276:immunology / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D014158:Transcription, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000187:drug effects / Q000235:genetics*; D000099222:betaIG-H3 Protein
D016572:Cyclosporine; D016326:Extracellular Matrix Proteins; D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D000099222:betaIG-H3 Protein