Abstract
The blockade of angiotensin II (Ang II) is a major therapeutic strategy for diabetic nephropathy. The main roles of Ang II in renal disease are mediated via the Ang type 1 receptor (AT1R). Upregulation of clusterin/apolipoprotein J has been reported in nephropathy models, suggesting it has a protective role in nephropathogenesis. Here, we studied how clusterin acts against Ang II-induced renal fibrosis. Levels of AT1R and fibrotic markers in clusterin-/- mice and Ang II infused rats transfected with an adenovirus encoding clusterin were evaluated by immunoblot analysis, real time RT-PCR, and immunohistochemical staining. The effect of clusterin on renal fibrosis was evaluated in NRK-52E cells, a cultured renal tubular epithelial cell line, using immunoblot analysis and real time RT-PCR. Nuclear localization of NF-κB was evaluated using immunofluorecence and co-immunoprecipitation. Renal fibrosis and expression of AT1R was higher in the kidneys of clusterin-/- mice than in those of wild-type mice. Furthermore, loss of clusterin accelerated Ang II-stimulated renal fibrosis and AT1R expression. Overexpression of clusterin in proximal tubular epithelial cells decreased the levels of Ang II-stimulated fibrotic markers and AT1R. Moreover, intrarenal delivery of clusterin attenuated Ang II-mediated expression of fibrotic markers and AT1R in rats. Fluorescence microscopy and co-immunoprecipitation in conjunction with western blot revealed that clusterin inhibited Ang II-stimulated nuclear localization of p-NF-κB via a direct physical interaction and subsequently decreased the AT1R level in proximal tubular epithelial cells. These data suggest that clusterin attenuates Ang II-induced renal fibrosis by inhibition of NF-κB activation and subsequent downregulation of AT1R. This study raises the possibility that clusterin could be used as a therapeutic target for Ang II-induced renal diseases.
Highlights
Renal fibrosis, mainly characterized by extracellular matrix (ECM) proteins deposition, is the universal mechanism of chronic kidney disease [1,2]
It has been shown that in cultured renal cells, Angiotensin II (Ang II) induces protein expressions which mainly play roles in cellular growth and matrix formation [4]; this effect is mainly mediated by the release of transforming growth factor b (TGF-b) [5] and this process can be partially attenuated by Ang-converting enzyme (ACE) inhibitors and Ang type 1 (AT1) antagonists [6,7]
We focused on the role of clusterin in Ang II-induced renal fibrosis, which is more relevant to the pathophysiology of renal diseases
Summary
Mainly characterized by extracellular matrix (ECM) proteins deposition, is the universal mechanism of chronic kidney disease [1,2]. It has been shown that in cultured renal cells, Ang II induces protein expressions which mainly play roles in cellular growth and matrix formation [4]; this effect is mainly mediated by the release of transforming growth factor b (TGF-b) [5] and this process can be partially attenuated by Ang-converting enzyme (ACE) inhibitors and Ang type 1 (AT1) antagonists [6,7]. Ang II is involved in recruitment of inflammatory cells and increases the expression levels of chemokines, adhesion molecules, cytokines, and other growth factors [8,9]. ACE inhibitors and AT1 antagonists ameliorate kidney disease progression in humans and animal models by reducing proteinuria, inflammatory cell infiltration and fibrosis [10,11]. It has been found that NF-kB is a key upstream mediator of diabetic nephropathy which is provoked by multiple pathophysiologies such as inappropriate hyperactivation of Ang II, increased synthesis of advanced glycation end products and reactive oxygen species [13,15,16]
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