| First Author | Jung GS | Year | 2014 |
| Journal | PLoS One | Volume | 9 |
| Issue | 8 | Pages | e105635 |
| PubMed ID | 25148511 | Mgi Jnum | J:221084 |
| Mgi Id | MGI:5637899 | Doi | 10.1371/journal.pone.0105635 |
| Citation | Jung GS, et al. (2014) Clusterin/apolipoprotein J attenuates angiotensin II-induced renal fibrosis. PLoS One 9(8):e105635 |
| abstractText | 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-kappaB 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-kappaB 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-kappaB 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. |
