Heterozygous disruption of activin receptor-like kinase 1 is associated with increased renal fibrosis in a mouse model of obstructive nephropathy.
Tubulointerstitial fibrosis is characterized by an accumulation of extracellular matrix in the renal interstitium, myofibroblast activation, cell infiltration, and tubular cell apoptosis, leading to chronic renal failure. Activin receptor-like kinase 1 (ALK1) is a transforming growth factor-β1 type I receptor with a pivotal role in endothelial proliferation and migration, but its role in the development of renal fibrosis is unknown. To assess this we used the unilateral ureteral obstruction model of tubulointerstitial fibrosis in ALK1 haploinsufficient (ALK1(+/-)) and wild-type mice. After 15 days, there was an increase in extracellular matrix protein expression in the obstructed kidneys from both ALK1(+/+) and ALK1(+/-) mice, but obstructed kidneys from ALK1(+/-) mice showed significantly higher expression of type I collagen than those from wild-type mice. Ureteral obstruction increased kidney myofibroblasts markers (α-smooth muscle actin and S100A4), without differences between mouse genotypes. ALK1 expression was increased after ureteral obstruction, and this increased expression was located in myofibroblasts. Moreover, cultured renal fibroblasts from ALK1(+/-) mice expressed more collagen type I and fibronectin than fibroblasts derived from wild-type mice. Thus, ALK1 modulates obstruction-induced renal fibrosis by increased extracellular matrix synthesis in myofibroblasts, but without differences in myofibroblast number.
1] Unidad de Fisiopatología Renal y Cardiovascular, Instituto "Reina Sofía" de Investigación Nefrológica, Departamento de Fisiología y Farmacología, Universidad de Salamanca, Salamanca, Spain [2] Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain.
José M
JM
Muñoz-Félix
1] Unidad de Fisiopatología Renal y Cardiovascular, Instituto "Reina Sofía" de Investigación Nefrológica, Departamento de Fisiología y Farmacología, Universidad de Salamanca, Salamanca, Spain [2] Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain.
José M
JM
López-Novoa
1] Unidad de Fisiopatología Renal y Cardiovascular, Instituto "Reina Sofía" de Investigación Nefrológica, Departamento de Fisiología y Farmacología, Universidad de Salamanca, Salamanca, Spain [2] Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain [3] Instituto de Estudios de Ciencias de la Salud de Castilla y León (IECSCYL), Unidad de Investigación, Hospital Universitario de Salamanca, Salamanca, Spain.
Carlos
C
Martínez-Salgado
D000199:Actins / Q000378:metabolism; D030201:Activin Receptors, Type I / Q000172:deficiency* / Q000235:genetics; D030301:Activin Receptors, Type II; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis; D057895:Haploinsufficiency; D006579:Heterozygote; D007668:Kidney / Q000201:enzymology* / Q000473:pathology; D007674:Kidney Diseases / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058628:Myofibroblasts / Q000201:enzymology / Q000473:pathology; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000378:metabolism; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014517:Ureteral Obstruction / Q000150:complications* / Q000201:enzymology / Q000235:genetics
C558396:Acta2 protein, mouse; D000199:Actins; D015415:Biomarkers; D024042:Collagen Type I; D005353:Fibronectins; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C470944:S100a4 protein, mouse; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; C498931:Acvrl1 protein, mouse