Up-regulation of the kinin B2 receptor pathway modulates the TGF-β/Smad signaling cascade to reduce renal fibrosis induced by albumin.

Areli Cárdenas, Javiera Campos, Pamela Ehrenfeld, Sergio Mezzano, Marta Ruiz-Ortega, Carlos D Figueroa, Leopoldo Ardiles

Peptides 2015 Nov

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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. Copyright © 2015 Elsevier Inc. All rights reserved.

Citation

Areli Cárdenas, Javiera Campos, Pamela Ehrenfeld, Sergio Mezzano, Marta Ruiz-Ortega, Carlos D Figueroa, Leopoldo Ardiles. Up-regulation of the kinin B2 receptor pathway modulates the TGF-β/Smad signaling cascade to reduce renal fibrosis induced by albumin. Peptides. 2015 Nov;73:7-19