title: Unfolded protein response causes a phenotypic shift of inflamed glomerular cells toward redifferentiation through dual blockade of Akt and Smad signaling pathways.
abstract: During recovery from acute glomerulonephritis, cell proliferation, matrix expansion, and expression of the dedifferentiation marker α-smooth muscle actin (α-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 α-SMA. Consistent with this in vivo result, induction of the UPR suppressed cell proliferation and transcriptional expression of type IV collagen (ColIV) and α-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 α-SMA. Translational suppression via the eIF2α 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.
authors.affiliation: Department of Molecular Signaling, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Johno
authors.forename: Shotaro
authors.initials: S
authors.lastname: Nakajima
authors.forename: Hironori
authors.initials: H
authors.lastname: Kato
authors.forename: Jian
authors.initials: J
authors.lastname: Yao
authors.forename: Adrienne W
authors.initials: AW
authors.lastname: Paton
authors.forename: James C
authors.initials: JC
authors.lastname: Paton
authors.forename: Ryohei
authors.initials: R
authors.lastname: Katoh
authors.forename: Fujio
authors.initials: F
authors.lastname: Shimizu
authors.forename: Masanori
authors.initials: M
authors.lastname: Kitamura
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D024141:Collagen Type IV / Q000378:metabolism; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D007249:Inflammation / Q000473:pathology*; D007678:Kidney Glomerulus / Q000201:enzymology* / Q000473:pathology*; D008297:Male; D008954:Models, Biological; D010641:Phenotype; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism*; D014158:Transcription, Genetic; D056811:Unfolded Protein Response / Q000235:genetics
chemical_list: D000199:Actins; D024141:Collagen Type IV; D015852:Eukaryotic Initiation Factor-2; D051057:Proto-Oncogene Proteins c-akt; D051785:Smad Proteins; C498862:Acta2 protein, rat