title: Calcium oxalate crystals and oxalate induce an epithelial-to-mesenchymal transition in the proximal tubular epithelial cells: Contribution to oxalate kidney injury.
abstract: TGF-β1 is the main mediator of epithelial-to-mesenchymal transition (EMT). Hyperoxaluria induces crystalluria, interstitial fibrosis, and progressive renal failure. This study analyzed whether hyperoxaluria is associated with TGF-β1 production and kidney fibrosis in mice and if oxalate or calcium oxalate (CaOx) could induce EMT in proximal tubule cells (HK2) and therefore contribute to the fibrotic process. Hyperoxaluria was induced by adding hydroxyproline and ethylene glycol to the mice's drinking water for up to 60 days. Renal function and oxalate and urinary crystals were evaluated. Kidney collagen production and TGF-β1 expression were assessed. EMT was analyzed in vitro according to TGF-β1 production, phenotypic characterization, invasion, cell migration, gene and protein expression of epithelial and mesenchymal markers. Hyperoxaluric mice showed a decrease in renal function and an increase in CaOx crystals and Ox urinary excretion. The deposition of collagen in the renal interstitium was observed. HK2 cells stimulated with Ox and CaOx exhibited a decreased expression of epithelial as well as increased expression mesenchymal markers; these cells presented mesenchymal phenotypic changes, migration, invasiveness capability and TGF-β1 production, characterizing EMT. Treatment with BMP-7 or its overexpression in HK2 cells was effective at preventing it. This mechanism may contribute to the fibrosis observed in hyperoxaluria.
authors.affiliation: Department of Medicine, Nephrology Division, Universidade Federal de São Paulo (UNIFESP), São Paulo, SP, Brazil.
authors.forename: Marcia Bastos
authors.initials: MB
authors.lastname: Convento
authors.affiliation: Department of Medicine, Nephrology Division, Universidade Federal de São Paulo (UNIFESP), São Paulo, SP, Brazil.
authors.forename: Edson Andrade
authors.initials: EA
authors.lastname: Pessoa
authors.affiliation: Department of Medicine, Nephrology Division, Universidade Federal de São Paulo (UNIFESP), São Paulo, SP, Brazil.
authors.forename: Edgar
authors.initials: E
authors.lastname: Cruz
authors.affiliation: Department of Medicine, Nephrology Division, Universidade Federal de São Paulo (UNIFESP), São Paulo, SP, Brazil.
authors.forename: Maria Aparecida
authors.initials: MA
authors.lastname: da Glória
authors.affiliation: Department of Medicine, Nephrology Division, Universidade Federal de São Paulo (UNIFESP), São Paulo, SP, Brazil.
authors.forename: Nestor
authors.initials: N
authors.lastname: Schor
authors.affiliation: Department of Medicine, Nephrology Division, Universidade Federal de São Paulo (UNIFESP), São Paulo, SP, Brazil.|Postgraduate Program, Health Sciences, CBS, Universidade Cruzeiro do Sul, São Paulo, Brazil.
authors.forename: Fernanda Teixeira
authors.initials: FT
authors.lastname: Borges
mesh_terms: D000818:Animals; D002129:Calcium Oxalate / Q000008:administration & dosage*; D002465:Cell Movement; D058750:Epithelial-Mesenchymal Transition; D019855:Ethylene Glycol / Q000008:administration & dosage; D005355:Fibrosis / Q000139:chemically induced / Q000473:pathology; D006909:Hydroxyproline / Q000008:administration & dosage; D006959:Hyperoxaluria / Q000139:chemically induced; D007668:Kidney / Q000293:injuries*; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D008810:Mice, Inbred C57BL; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D053773:Transforming Growth Factor beta1; D002129:Calcium Oxalate; D019855:Ethylene Glycol; D006909:Hydroxyproline