| First Author | Johno H | Year | 2012 |
| Journal | Am J Pathol | Volume | 181 |
| Issue | 6 | Pages | 1977-90 |
| PubMed ID | 23031256 | Mgi Jnum | J:190293 |
| Mgi Id | MGI:5448567 | Doi | 10.1016/j.ajpath.2012.08.015 |
| Citation | Johno H, et al. (2012) Unfolded protein response causes a phenotypic shift of inflamed glomerular cells toward redifferentiation through dual blockade of Akt and Smad signaling pathways. Am J Pathol 181(6):1977-90 |
| abstractText | During recovery from acute glomerulonephritis, cell proliferation, matrix expansion, and expression of the dedifferentiation marker alpha-smooth muscle actin (alpha-SMA) subside spontaneously. However, the molecular mechanisms underlying this recovery process remain elusive. In mesangioproliferative glomerulonephritis, the unfolded protein response (UPR) is induced in activated, dedifferentiated mesangial cells. We investigated the role of the UPR in mesangial cell deactivation and redifferentiation and found that, during experimental glomerulonephritis in rats, reinforcement of the UPR significantly attenuated mesangial cell proliferation, matrix expansion, and expression of alpha-SMA. Consistent with this in vivo result, induction of the UPR suppressed cell proliferation and transcriptional expression of type IV collagen (ColIV) and alpha-SMA in activated mesangial cells. The UPR reduced phosphorylation of Akt in vitro and in vivo, and it was responsible for attenuation of cell proliferation. The UPR also preferentially depressed levels of total and phosphorylated Smads without affecting transcriptional levels, and it was responsible for suppression of ColIV and alpha-SMA. Translational suppression via the eIF2alpha pathway, but not proteasome-mediated protein degradation, was responsible for the down-regulation of Smads. These results suggest the novel potential of the UPR to facilitate a phenotypic shift of activated glomerular cells toward deactivation and redifferentiation. The UPR may serve as endogenous machinery that supports recovery of glomeruli from acute inflammation. |
