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Enhanced TGF-b/Smad signaling in the early stage of diabetic nephropathy is independent of the AT1a receptor

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Abstract

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.

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Authors and Affiliations

  1. Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama, 700-8558, Japan

    Yuko Okazaki, Yasushi Yamasaki, Haruhito A. Uchida, Kazunori Okamoto, Minoru Satoh, Keisuke Maruyama, Yohei Maeshima, Hitoshi Sugiyama & Hirofumi Makino

  2. Riken Kobe Institute Center for Developmental Biology, Kobe, Hyogo, Japan

    Takeshi Sugaya

  3. Division of Nephrology, Department of Internal Medicine, Kawasaki Medical School, Kurashiki, Okayama, Japan

    Naoki Kashihara

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  1. Yuko Okazaki
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  2. Yasushi Yamasaki
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  3. Haruhito A. Uchida
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  4. Kazunori Okamoto
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  5. Minoru Satoh
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  11. Hirofumi Makino
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Correspondence to Yuko Okazaki.

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Okazaki, Y., Yamasaki, Y., Uchida, H. et al. Enhanced TGF-b/Smad signaling in the early stage of diabetic nephropathy is independent of the AT1a receptor. Clin Exp Nephrol 11, 77–87 (2007). https://doi.org/10.1007/s10157-006-0456-1

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  • DOI: https://doi.org/10.1007/s10157-006-0456-1

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