TY - JOUR
T1 - Enhanced TGF-β/Smad signaling in the early stage of diabetic nephropathy is independent of the AT1a receptor
AU - Okazaki, Yuko
AU - Yamasaki, Yasushi
AU - Uchida, Haruhito A.
AU - Okamoto, Kazunori
AU - Satoh, Minoru
AU - Maruyama, Keisuke
AU - Maeshima, Yohei
AU - Sugiyama, Hitoshi
AU - Sugaya, Takeshi
AU - Kashihara, Naoki
AU - Makino, Hirofumi
PY - 2007/3
Y1 - 2007/3
N2 - Background. Angiotensin II (AII) and transforming growth factor-β (TGF-β) are closely involved in the pathogenesis of diabetic nephropathy (DN). AII is known to induce TGF-β production in resident renal cells, including glomerular mesangial cells and tubular epithelial cells. TGF-β receptor types I and II (TGF-βRI, II) are up-regulated in the diabetic kidney. The aim of this study was to clarify the role of AII in the regulation of the TGF-β system in the early stage of DN using AII type1a receptor-deficient(AT1a-/-) mice. Methods. We investigated the expression of TGF-β1, TGF-βRI, II, and Smad signaling in AT1a -/- mice with streptozotocin (STZ)-induced DN. Mice were killed 10 and 20 days after the induction of hyperglycemia. The expression of TGF-β receptors was analyzed by immunohistochemical staining and reverse transcriptase-polymerase chain reaction (RT-PCR). TGF-β-specific Smad signaling was analyzed by electrophoretic mobility shift assay and Western blotting. Results. The expression of both TGF-βRI and RII was up-regulated in the glomerular tufts and vasculature in diabetic AT1a+/+ mice kidney by immunohistochemistry. RT-PCR revealed that mRNAs for TGF-βRI and RII were also up-regulated. Smad2 and 4 protein levels were reduced in the renal cortex after the induction of diabetes, with an increase of Smad 3/4 complex in the nucleus. The expression of TGF-β receptors increased in both diabetic AT1a-/- and AT1a+/+ mice. Smad signaling in AT1a -/- mice was also enhanced. Conclusions. Our results suggest that the complete blockade of the AT1a-mediated pathway has a minimal effect on the enhanced TGF-β/Smad signaling in the early stage of DN, at least in the AT1a-/- model.
AB - Background. Angiotensin II (AII) and transforming growth factor-β (TGF-β) are closely involved in the pathogenesis of diabetic nephropathy (DN). AII is known to induce TGF-β production in resident renal cells, including glomerular mesangial cells and tubular epithelial cells. TGF-β receptor types I and II (TGF-βRI, II) are up-regulated in the diabetic kidney. The aim of this study was to clarify the role of AII in the regulation of the TGF-β system in the early stage of DN using AII type1a receptor-deficient(AT1a-/-) mice. Methods. We investigated the expression of TGF-β1, TGF-βRI, II, and Smad signaling in AT1a -/- mice with streptozotocin (STZ)-induced DN. Mice were killed 10 and 20 days after the induction of hyperglycemia. The expression of TGF-β receptors was analyzed by immunohistochemical staining and reverse transcriptase-polymerase chain reaction (RT-PCR). TGF-β-specific Smad signaling was analyzed by electrophoretic mobility shift assay and Western blotting. Results. The expression of both TGF-βRI and RII was up-regulated in the glomerular tufts and vasculature in diabetic AT1a+/+ mice kidney by immunohistochemistry. RT-PCR revealed that mRNAs for TGF-βRI and RII were also up-regulated. Smad2 and 4 protein levels were reduced in the renal cortex after the induction of diabetes, with an increase of Smad 3/4 complex in the nucleus. The expression of TGF-β receptors increased in both diabetic AT1a-/- and AT1a+/+ mice. Smad signaling in AT1a -/- mice was also enhanced. Conclusions. Our results suggest that the complete blockade of the AT1a-mediated pathway has a minimal effect on the enhanced TGF-β/Smad signaling in the early stage of DN, at least in the AT1a-/- model.
KW - Diabetic nephropathy
KW - Smad
KW - TGF-β receptor type I and type II
KW - Transforming growth factor-β
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U2 - 10.1007/s10157-006-0456-1
DO - 10.1007/s10157-006-0456-1
M3 - Article
C2 - 17385003
AN - SCOPUS:33947511782
SN - 1342-1751
VL - 11
SP - 77
EP - 87
JO - Clinical and Experimental Nephrology
JF - Clinical and Experimental Nephrology
IS - 1
ER -
