title: Epithelial calreticulin up-regulation promotes profibrotic responses and tubulointerstitial fibrosis development.
abstract: Renal fibrosis is the common anatomical feature underlying the progression of chronic kidney disease, a leading cause of morbidity and mortality worldwide. In a previous study, we demonstrated that during development of renal fibrosis in a rat model of unilateral ureteric obstruction, calreticulin (CRT) is up-regulated in tubular epithelial cells (TECs). In the present study, we used in vitro and in vivo approaches to examine the role of CRT in TECs and its contribution to the progression of fibrosis. In cultured renal TECs, CRT overexpression induced acquisition of an altered, profibrotic cellular phenotype. Consistently, the opposite effects were observed for CRT knockdown. Subsequently, we confirmed that critical changes observed in vitro were also apparent in tubular cells in vivo in the animal model of unilateral ureteric obstruction. In agreement with these results, we demonstrate that substantial (50%) reduction in the expression of CRT reduced the development of tubulointerstitial fibrosis at a comparable level through regulation of inflammation, transcriptional activation, transforming growth factor β1-associated effects, and apoptosis. In summary, our findings establish that CRT is critically involved in the molecular mechanisms that drive renal fibrosis progression and indicate that inhibition of CRT expression might be a therapeutic target for reduction of fibrosis and chronic kidney disease development.
authors.affiliation: Section of Histology, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
authors.forename: Niki
authors.initials: N
authors.lastname: Prakoura
authors.affiliation: Section of Histology, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
authors.forename: Panagiotis K
authors.initials: PK
authors.lastname: Politis
authors.affiliation: Department of Biochemistry, Wakayama Medical University, Wakayama, Japan.
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Ihara
authors.affiliation: Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Marek
authors.initials: M
authors.lastname: Michalak
authors.affiliation: Section of Histology, Biomedical Research Foundation of the Academy of Athens, Athens, Greece. Electronic address: acharonis@bioacademy.gr.
authors.forename: Aristidis S
authors.initials: AS
authors.lastname: Charonis
mesh_terms: D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000378:metabolism; D037282:Calreticulin / Q000378:metabolism*; D002460:Cell Line; D002465:Cell Movement; D049109:Cell Proliferation; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D059865:Endoplasmic Reticulum Stress; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis; D055785:Gene Knockdown Techniques; D006579:Heterozygote; D006801:Humans; D007674:Kidney Diseases / Q000378:metabolism* / Q000473:pathology*; D007684:Kidney Tubules / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008648:Mesoderm / Q000378:metabolism / Q000473:pathology; D051379:Mice; D051381:Rats; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D015854:Up-Regulation; D014517:Ureteral Obstruction / Q000378:metabolism / Q000473:pathology
chemical_list: D015415:Biomarkers; D037282:Calreticulin; D053773:Transforming Growth Factor beta1; D003094:Collagen