HSP47 regulates ECM accumulation in renal proximal tubular cells induced by TGF-β1 through ERK1/2 and JNK MAPK pathways.
Heat shock protein (HSP)47 is a collagen-specific molecular chaperone that is essential for the biosynthesis of collagen molecules. It is likely that increased levels of HSP47 contribute to the assembly of procollagen and thereby cause an excessive accumulation of collagens in disease processes associated with fibrosis. Although HSP47 promotes renal fibrosis, the underlying mechanism and associated signaling events have not been clearly delineated. We examined the role of HSP47 in renal fibrosis using a rat unilateral ureteral obstruction model and transforming growth factor (TGF)-β(1)-treated human proximal tubular epithelial (HK-2) cells. An upregulation of HSP47 in both in vivo and in vitro models was observed, which correlated with the increased synthesis of extracellular matrix (ECM) proteins and expression of tissue-type plasminogen activator inhibitor (PAI)-1. Blockade of HSP47 by short interfering RNA suppressed the expression of ECM proteins and PAI-1. In addition, TGF-β(1)-induced HSP47 expression in HK-2 cells was attenuated by ERK1/2 and JNK MAPK inhibitors. These data suggest that ERK1/2 and JNK signaling events are involved in modulating the expression of HSP47, the chaperoning effect of which on TGF-β(1) would ultimately contribute to renal fibrosis by enhancing the synthesis and deposition of ECM proteins.
Department of Nephrology, The Second Xiangya Hospital, Kidney Institute of Central South University, No. 139 Remin Middle Rd., Changsha, Hunan, China.
Hong-bo
HB
Xiao
Rui-hong
RH
Liu
Guang-hui
GH
Ling
Li
L
Xiao
Yuan-chen
YC
Xia
Fu-you
FY
Liu
Jun
J
Li
Ying-hong
YH
Liu
Qin-kai
QK
Chen
Jin-lei
JL
Lv
Ming
M
Zhan
Shi-kun
SK
Yang
Yashpal S
YS
Kanwar
Lin
L
Sun
D000328:Adult; D000818:Animals; D002460:Cell Line; D024042:Collagen Type I / Q000096:biosynthesis; D024141:Collagen Type IV / Q000096:biosynthesis; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis*; D005355:Fibrosis; D050958:HSP47 Heat-Shock Proteins / Q000502:physiology*; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3 / Q000502:physiology; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D015854:Up-Regulation; D014517:Ureteral Obstruction / Q000503:physiopathology
D024042:Collagen Type I; D024141:Collagen Type IV; D016326:Extracellular Matrix Proteins; D050958:HSP47 Heat-Shock Proteins; D017395:Plasminogen Activator Inhibitor 1; D034741:RNA, Small Interfering; D053773:Transforming Growth Factor beta1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3