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.
Sun
Bo Kyung
BK
Department of Internal Medicine, Cell Death Disease Research Center, Catholic University of Korea, Seoul, South Korea.
Li
Can
C
Lim
Sun Woo
SW
Jung
Ju Young
JY
Lee
Suk Hee
SH
Kim
In San
IS
Kim
Yong Soo
YS
Kim
Jin
J
Bang
Byung Kee
BK
Yang
Chul Woo
CW
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