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Regulation of renal fibrosis by the transforming growth factor beta-1 receptor Alk1

Authors:

Carlos Martínez-Salgado ,

Unidad de Fisiopatología Renal y Cardiovascular, Instituto “Reina Sofía” de Investigación Nefrológica, Departamento de Fisiología y Farmacología, Universidad de Salamanca, Salamanca, Spain; Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain; Instituto de Estudios de Ciencias de la Salud de Castilla y León (IECSCYL), Unidad de Investigación, Hospital Universitario de Salamanca, Salamanca, Spain, ES
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José M. Muñoz-Félix,

Unidad de Fisiopatología Renal y Cardiovascular, Instituto “Reina Sofía” de Investigación Nefrológica, Departamento de Fisiología y Farmacología, Universidad de Salamanca, Salamanca, Spain; Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain, ES
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Nuria Perretta-Tejedor,

Unidad de Fisiopatología Renal y Cardiovascular, Instituto “Reina Sofía” de Investigación Nefrológica, Departamento de Fisiología y Farmacología, Universidad de Salamanca, Salamanca, Spain; Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain; Instituto de Estudios de Ciencias de la Salud de Castilla y León (IECSCYL), Unidad de Investigación, Hospital Universitario de Salamanca, Salamanca, Spain, ES
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López Novoa

Unidad de Fisiopatología Renal y Cardiovascular, Instituto “Reina Sofía” de Investigación Nefrológica, Departamento de Fisiología y Farmacología, Universidad de Salamanca, Salamanca, Spain; Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain, ES
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Abstract

Tubulointerstitial fibrosis –a common end-stage feature of chronic kidney disease- is characterized by the presence of renal myofibroblasts and excessive accumulation of extracellular matrix proteins (ECM) in the renal tubular interstitium. The cytokine transforming growth factor beta 1 (TGF-β1) promotes myofibroblast activation and ECM proteins expression through intracellular Smads activation, having an important role in renal fibrosis. We have recently reported that the heterozygous disruption of the TGF-β1 receptor activin receptor-like kinase 1 (ALK1) leads to an increase in TGF-β induced renal fibrosis after ureteral obstruction. Thus, we analyzed the effect of ALK1 heterozygosity in TGF-β1 induced signaling and its consequent fibrotic response in mouse embryonic fibroblasts (MEFs). We have analyzed Smad signaling pathaways in ALK1 heterozygous MEFs (ALK1+/-) and their respective controls (ALK1+/+) in basal conditions and after TGF-β1 treatment by Western blot and immunofluorescence. Moreover, we have analyzed collagen I, fibronectin and connective tissue growth factor (CTGF) expression in basal conditions, after TGF-β1 stimulation and after ALK5 inhibition –with SB431542- and Smad3 inhibition –with SIS3-. TGF-β1 stimulation induced Smad2 and Smad3 phosphorylation and Smad2/3 translocation into the nucleus in ALK1+/+ and ALK1+/- MEFs, being this increase higher in ALK1+/- MEFs. Basal Smad2 and Smad3 phosphorylation was higher in ALK1 heterozygous fibroblasts. TGF-β1 stimulation did not induce Smad1 phosphorylation in ALK1+/- MEFs and a very small Smad1 phosphorylation in ALK1+/- MEFs. ALK1 heterozygous MEFs expressed more collagen I, fibronectin and CTGF than their respective controls in basal conditions. Stimulation with TGF-β1 lead to an increase in collagen I, fibronectin and CTGF, being the increase in fibronectin and CTGF higher in ALK1+/- MEFs. Inhibition of ALK5 and Smad3 reversed the ALK1+/- phenotype. Summarizing, ALK1 heterozygous disruption leads to an impairment of TGF-β1 signaling and increased TGF-β1-induced fibrotic response in mouse embryonic fibroblasts.
How to Cite: Martínez-Salgado, C., M. Muñoz-Félix, J., Perretta-Tejedor, N. and Novoa, L., 2015. Regulation of renal fibrosis by the transforming growth factor beta-1 receptor Alk1. European Journal of Molecular & Clinical Medicine, 2(2), p.69. DOI: http://doi.org/10.1016/j.nhtm.2014.11.050
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Published on 07 Feb 2015.
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