title: Tubular expression of heat-shock protein 27 inhibits fibrogenesis in obstructive nephropathy.
abstract: Morphological changes that occur during kidney injury involve actin skeleton remodeling. Here we tested whether heat-shock protein 27 (HSP27), a small stress response protein involved in cytoskeletal remodeling, protects the kidney from tubulointerstitial fibrosis in obstructive nephropathy. Tubular cell HSP27 immunostaining was significantly increased in human kidneys with ureteropelvic junction obstruction, supporting the clinical relevance of our studies. To develop an animal model for mechanistic studies, we generated transgenic mice that specifically overexpress human HSP27 in renal tubules, under the kidney androgen-regulated protein promoter, and determined the effects of HSP27 overexpression on epithelial-to-mesenchymal transition and tubulointerstitial fibrosis following unilateral ureteral obstruction. This was associated with decreased fibrogenesis as evidenced by significant declines in phosphorylated p38MAPK, collagen III, α-smooth muscle actin, 4-hydroxynonenal, and reduced trichrome staining following obstruction. Notably, E-cadherin and β-catenin remained at the cell membrane of tubular cells in transgenic mice with an obstructed ureter. Monocyte/macrophage infiltration, however, was not significantly affected in these transgenic mice. Thus, tubular HSP27 inhibits fibrogenesis in obstructive nephropathy. Further studies are needed to determine pathways regulating the interactions between HSP27 and the E-cadherin-β-catenin complex.
authors.affiliation: Division of Nephrology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.
authors.forename: Aparna
authors.initials: A
authors.lastname: Vidyasagar
authors.forename: Shannon R
authors.initials: SR
authors.lastname: Reese
authors.forename: Omeed
authors.initials: O
authors.lastname: Hafez
authors.forename: Ling-Jin
authors.initials: LJ
authors.lastname: Huang
authors.forename: William F
authors.initials: WF
authors.lastname: Swain
authors.forename: Lynn M
authors.initials: LM
authors.lastname: Jacobson
authors.forename: Jose R
authors.initials: JR
authors.lastname: Torrealba
authors.forename: Pierre-Emmanuel
authors.initials: PE
authors.lastname: Chammas
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Wilson
authors.forename: Arjang
authors.initials: A
authors.lastname: Djamali
mesh_terms: D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D024061:Collagen Type III / Q000378:metabolism; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D005355:Fibrosis; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007674:Kidney Diseases / Q000378:metabolism* / Q000473:pathology*; D007684:Kidney Tubules / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D014517:Ureteral Obstruction / Q000378:metabolism* / Q000473:pathology*; D051176:beta Catenin / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D015820:Cadherins; D024061:Collagen Type III; D055551:HSP27 Heat-Shock Proteins; D051176:beta Catenin; D048051:p38 Mitogen-Activated Protein Kinases