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Clin Exp Nephrol. 2007 Mar;11(1):77-87. Epub 2007 Mar 28.

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

Author information

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. yahman-a-and-y@r5.dion.ne.jp

Abstract

BACKGROUND:

Angiotensin II (AII) and transforming growth factor-beta (TGF-beta) are closely involved in the pathogenesis of diabetic nephropathy (DN). AII is known to induce TGF-beta production in resident renal cells, including glomerular mesangial cells and tubular epithelial cells. TGF-beta receptor types I and II (TGF-betaRI, 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-beta system in the early stage of DN using AII type1a receptor-deficient(AT1a(-/-)) mice.

METHODS:

We investigated the expression of TGF-beta1, TGF-betaRI, 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-beta receptors was analyzed by immunohistochemical staining and reverse transcriptase-polymerase chain reaction (RT-PCR). TGF-beta-specific Smad signaling was analyzed by electrophoretic mobility shift assay and Western blotting.

RESULTS:

The expression of both TGF-betaRI 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-betaRI 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-beta 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-beta/Smad signaling in the early stage of DN, at least in the AT1a(-/-) model.

PMID:
17385003
DOI:
10.1007/s10157-006-0456-1
[Indexed for MEDLINE]

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