Heme oxygenase-1 deficiency promotes epithelial-mesenchymal transition and renal fibrosis.
Induction of heme oxygenase-1 (HO-1) is associated with potential antifibrogenic effects. The effects of HO-1 expression on epithelial-mesenchymal transition (EMT), which plays a critical role in the development of renal fibrosis, are unknown. In this study, HO-1(-/-) mice demonstrated significantly more fibrosis after 7 d of unilateral ureteral obstruction compared with wild-type mice, despite similar degrees of hydronephrosis. The obstructed kidneys of HO-1(-/-) mice also had greater macrophage infiltration and renal tubular TGF-beta1 expression than wild-type mice. In addition, the degree of EMT was more extensive in obstructed HO-1(-/-) kidneys, as assessed by alpha-smooth muscle actin and expression of S100A4 in proximal tubular epithelial cells. In vitro studies using proximal tubular cells isolated from HO-1(-/-) and wild-type kidneys confirmed these observations. In conclusion, HO-1 deficiency is associated with increased fibrosis, tubular TGF-beta1 expression, inflammation, and enhanced EMT in obstructive kidney disease. Modulation of the HO-1 pathway may provide a new therapeutic approach to progressive renal diseases.
Kie
Jeong-Hae
JH
Department of Medicine, Division of Nephrology, Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
Kapturczak
Matthias H
MH
Traylor
Amie
A
Agarwal
Anupam
A
Hill-Kapturczak
Nathalie
N
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D054338:Cell Transdifferentiation; D002478:Cells, Cultured; D005355:Fibrosis; D051547:Heme Oxygenase-1 / Q000172:deficiency*; D007668:Kidney / Q000473:pathology*; D007687:Kidney Tubules, Proximal / Q000473:pathology; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009400:Nephrosclerosis / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D014517:Ureteral Obstruction
D015415:Biomarkers; D053773:Transforming Growth Factor beta1; D051547:Heme Oxygenase-1