SRY-related HMG box 9 regulates the expression of Col4a2 through transactivating its enhancer element in mesangial cells.
Accumulation of alpha1(IV) and alpha2(IV) collagen is one of the characteristic pathological changes in glomerulosclerosis. Although the Col4a2 gene is known to have a 0.3-kb critical enhancer element with the GAACAAT motif, which transcription factor binds and transactivates this motif has not been identified. In this study, we found that SRY-related HMG box 9 (SOX9) was bound to the GAACAAT motif in the Col4a2 enhancer in vitro and in vivo in mesangial cells. SOX9 strongly activated this enhancer when cotransfected with Col4a2 enhancer-promoter construct in mesangial cells and Swiss/3T3 cells. Mutation in the GAACAAT motif eliminated the activation by SOX9. Furthermore, transforming growth factor-beta (TGF-beta) treatment induced the expression of SOX9 and Col4a2, and a small interfering RNA against SOX9 reduced Col4a2 expression induced by TGF-beta treatment in mesangial cells. In vivo, we found that the expression of SOX9 was dramatically increased along with the expression of TGF-beta and Col4a2 in mouse nephrotoxic nephritis. These results indicate that SOX9 is essential for Col4a2 expression in mesangial cells and might be involved in the accumulation of alpha2(IV) collagen in experimental nephritis.
Sumi
Eriko
E
Department of Geriatric Medicine, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
Iehara
Noriyuki
N
Akiyama
Haruhiko
H
Matsubara
Takeshi
T
Mima
Akira
A
Kanamori
Hiroshi
H
Fukatsu
Atsushi
A
Salant
David J
DJ
Kita
Toru
T
Arai
Hidenori
H
Doi
Toshio
T
D000818:Animals; D002478:Cells, Cultured; D024141:Collagen Type IV / Q000235:genetics / Q000378:metabolism*; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006609:High Mobility Group Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D008297:Male; D050527:Mesangial Cells / Q000166:cytology / Q000502:physiology*; D051379:Mice; D009395:Nephritis, Interstitial / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D055758:SOX9 Transcription Factor; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
D024141:Collagen Type IV; D006609:High Mobility Group Proteins; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; C527933:Sox9 protein, mouse; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1