title: Up-regulation of the kinin B2 receptor pathway modulates the TGF-β/Smad signaling cascade to reduce renal fibrosis induced by albumin.
abstract: The presence of high protein levels in the glomerular filtrate plays an important role in renal fibrosis, a disorder that justifies the use of animal models of experimental proteinuria. Such models have proved useful as tools in the study of the pathogenesis of chronic, progressive renal disease. Since bradykinin and the kinin B2 receptor (B2R) belong to a renoprotective system with mechanisms still unclarified, we investigated its anti-fibrotic role in the in vivo rat model of overload proteinuria. Upon up-regulating the kinin system by a high potassium diet we observed reduction of tubulointerstitial fibrosis, decreased renal expression of α-smooth muscle actin (α-SMA) and vimentin, reduced Smad3 phosphorylation and increase of Smad7. These cellular and molecular effects were reversed by HOE-140, a specific B2R antagonist. In vitro experiments, performed on a cell line of proximal tubular epithelial cells, showed that high concentrations of albumin induced expression of mesenchymal biomarkers, in concomitance with increases in TGF-β1 mRNA and its functionally active peptide, TGF-β1. Stimulation of the tubule cells by bradykinin inhibited the albumin-induced changes, namely α-SMA and vimentin were reduced, and cytokeratin recovered together with increase in Smad7 levels and decrease in type II TGF-β1 receptor, TGF-β1 mRNA and its active fragment. The protective changes produced by bradykinin in vitro were blocked by HOE-140. The development of stable bradykinin analogues and/or up-regulation of the B2R signaling pathway may prove value in the management of chronic renal fibrosis in progressive proteinuric renal diseases.
authors.affiliation: Department of Nephrology, Universidad Austral de Chile, Valdivia, Chile.
authors.forename: Areli
authors.initials: A
authors.lastname: Cárdenas
authors.affiliation: Department of Nephrology, Universidad Austral de Chile, Valdivia, Chile.
authors.forename: Javiera
authors.initials: J
authors.lastname: Campos
authors.affiliation: Department of Anatomy, Histology and Pathology, Universidad Austral de Chile, Valdivia, Chile.
authors.forename: Pamela
authors.initials: P
authors.lastname: Ehrenfeld
authors.affiliation: Department of Nephrology, Universidad Austral de Chile, Valdivia, Chile.
authors.forename: Sergio
authors.initials: S
authors.lastname: Mezzano
authors.affiliation: IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Ruiz-Ortega
authors.affiliation: Department of Anatomy, Histology and Pathology, Universidad Austral de Chile, Valdivia, Chile.
authors.forename: Carlos D
authors.initials: CD
authors.lastname: Figueroa
authors.affiliation: Department of Nephrology, Universidad Austral de Chile, Valdivia, Chile. Electronic address: leopoldoardiles@gmail.com.
authors.forename: Leopoldo
authors.initials: L
authors.lastname: Ardiles
mesh_terms: D000418:Albumins / Q000009:adverse effects* / Q000494:pharmacology; D000818:Animals; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology; D065094:Bradykinin B2 Receptor Antagonists / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis; D006801:Humans; D011507:Proteinuria / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043782:Receptor, Bradykinin B2 / Q000096:biosynthesis*; D051906:Smad7 Protein / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D000418:Albumins; D065094:Bradykinin B2 Receptor Antagonists; D043782:Receptor, Bradykinin B2; D051906:Smad7 Protein; C497808:Smad7 protein, rat; C508962:Tgfb1 protein, rat; D053773:Transforming Growth Factor beta1; C065679:icatibant; D001920:Bradykinin
keywords: Fibrosis; Kidney; Kinins; Proteinuria; Smad proteins; Transforming growth factor beta1