TY - JOUR
T1 - Transforming growth factor-β1-mediated renal fibrosis is dependent on the regulation of transforming growth factor receptor 1 expression by let-7b
AU - Wang, Bo
AU - Jha, Jay C.
AU - Hagiwara, Shinji
AU - Mcclelland, Aaron D.
AU - Jandeleit-Dahm, Karin
AU - Thomas, Merlin C.
AU - Cooper, Mark E.
AU - Kantharidis, Phillip
PY - 2014/2
Y1 - 2014/2
N2 - Renal fibrosis results from excessive accumulation of extracellular matrix mainly driven by transforming growth factor-β1 (TGF-β1). Certain microRNAs have been implicated in this disease, and here we examine the role of let-7b. Rat proximal tubular epithelial cells (NRK52E) were treated with TGF-β1 for 3 days to assess the expression of markers of fibrosis and let-7b. These factors were also assessed in two mouse models representing early and more advanced diabetic nephropathy and in the non-diabetic adenine-induced renal fibrosis model. TGF-β1 downregulated the expression of let-7b and induced fibrogenesis in NRK52E cells. Ectopic expression of let-7b repressed TGF-β1 receptor 1 (TGFBR1) expression directly by targeting the two let-7b binding sites in the 3′-untranslated region of that gene, reduced expression of extracellular matrix proteins, decreased SMAD3 activity, and attenuated the profibrotic effects of TGF-β1. Knockdown of let-7b elevated TGFBR1 expression and mimicked some of the profibrotic effects of TGF-β1. Consistent with these observations, let-7b expression was also reduced in models of both diabetic and non-diabetic renal fibrosis with the upregulation of TGFBR1. Thus, let-7b microRNA represents a potential new target for the treatment of renal fibrosis in diabetic and non-diabetic nephropathy.
AB - Renal fibrosis results from excessive accumulation of extracellular matrix mainly driven by transforming growth factor-β1 (TGF-β1). Certain microRNAs have been implicated in this disease, and here we examine the role of let-7b. Rat proximal tubular epithelial cells (NRK52E) were treated with TGF-β1 for 3 days to assess the expression of markers of fibrosis and let-7b. These factors were also assessed in two mouse models representing early and more advanced diabetic nephropathy and in the non-diabetic adenine-induced renal fibrosis model. TGF-β1 downregulated the expression of let-7b and induced fibrogenesis in NRK52E cells. Ectopic expression of let-7b repressed TGF-β1 receptor 1 (TGFBR1) expression directly by targeting the two let-7b binding sites in the 3′-untranslated region of that gene, reduced expression of extracellular matrix proteins, decreased SMAD3 activity, and attenuated the profibrotic effects of TGF-β1. Knockdown of let-7b elevated TGFBR1 expression and mimicked some of the profibrotic effects of TGF-β1. Consistent with these observations, let-7b expression was also reduced in models of both diabetic and non-diabetic renal fibrosis with the upregulation of TGFBR1. Thus, let-7b microRNA represents a potential new target for the treatment of renal fibrosis in diabetic and non-diabetic nephropathy.
KW - chronic kidney disease
KW - diabetic nephropathy
KW - fibrosis
KW - micro-RNAs
KW - TGF-beta
UR - http://www.scopus.com/inward/record.url?scp=84895900338&partnerID=8YFLogxK
U2 - 10.1038/ki.2013.372
DO - 10.1038/ki.2013.372
M3 - Article
C2 - 24088962
AN - SCOPUS:84895900338
SN - 0085-2538
VL - 85
SP - 352
EP - 361
JO - Kidney International
JF - Kidney International
IS - 2
ER -