Prohibitin suppresses renal interstitial fibroblasts proliferation and phenotypic change induced by transforming growth factor-beta1.
Prohibitin (PHB), a potential tumor suppressor, has been shown to inhibit cell proliferation by repressing E2F-mediated transcription. But little is known about the role of PHB involved in tubulointerstitial fibrosis (TIF). Here, for the first time, we found PHB protein was positively expressed at normal renal tissues, strongly down-regulated in renal biopsy specimens, and negatively correlated with the expression of alpha-smooth-muscle actin (alpha-SMA) and with the degrees of tubulointerstitial lesions. Transforming growth factor-beta1 (TGF-beta1) is the most important profibrotic cytokine in the process of TIF and capable of inducing cell phenotypic change of interstitial fibroblasts characterized by the de novo expression of alpha-SMA. Confocal microscopy showed majority of PHB is located at cytoplasm as well as at nucleus in rat kidney fibroblasts cell (NRK-49F). As we found that PHB protein and mRNA expression were down-regulated in NRK-49F cells following TGF-beta1 stimulation. We used transient transfection to over-express PHB protein and found that cells with increased PHB levels had a significant reduction in the percentage entering cell cycle and abolished de novo expression of alpha-SMA following TGF-beta1 stimulation. Therefore, over-expression of PHB suppresses renal interstitial fibroblasts proliferation and cell phenotypic change induced by TGF-beta1, which indicates PHB as a potential therapeutic target to halt the progression of TIF.
Guo
Wei
W
Department of Nephrology, Children's Hospital of Fudan University, 183 Feng Lin Road, Shanghai, 200032, P.R. China.
Xu
Hong
H
Chen
Jing
J
Yang
Yong
Y
Jin
Jia Wei
JW
Fu
Rui
R
Liu
Hai Mei
HM
Zha
Xi Liang
XL
Zhang
Zhi Gang
ZG
Huang
Wen Yan
WY
D000199:Actins / Q000378:metabolism; D000293:Adolescent; D000818:Animals; D001706:Biopsy; D002467:Cell Nucleus / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects*; D005434:Flow Cytometry; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000473:pathology*; D008297:Male; D018613:Microscopy, Confocal; D009395:Nephritis, Interstitial / Q000473:pathology; D010641:Phenotype; D000091402:Prohibitins; D021381:Protein Transport / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*
D000199:Actins; C000717328:PHB protein, human; C000717332:Phb protein, rat; D000091402:Prohibitins; D012333:RNA, Messenger; D012097:Repressor Proteins; D053773:Transforming Growth Factor beta1