title: ASK1/p38 signaling in renal tubular epithelial cells promotes renal fibrosis in the mouse obstructed kidney.
abstract: Stress-activated kinases p38 MAPK and JNK promote renal fibrosis; however, how the pathways by which these kinases are activated in kidney disease remain poorly defined. Apoptosis signal-regulating kinase 1 (ASK1/MAPKKK5) is a member of the MAPKKK family that can induce activation of p38 and JNK. The present study examined whether ASK1 induces p38/JNK activation and renal fibrosis in unilateral ureteric obstruction (UUO) using wild-type (WT) and Ask1-deficient (Ask1(-/-)) mice. Basal p38 and JNK activation in WT kidneys was increased three- to fivefold in day 7 UUO mice in association with renal fibrosis. In contrast, there was no increase in p38 activation in Ask1(-/-) UUO mice, whereas JNK activation was only partially increased. The progressive increase in kidney collagen (hydroxyproline) content seen on days 7 and 12 of UUO in WT mice was significantly reduced in Ask1(-/-) UUO mice in association with reduced α-smooth muscle actin-positive myofibroblast accumulation. However, cultured WT and Ask1(-/-) renal fibroblasts showed equivalent proliferation and matrix production, indicating that ASK1 acts indirectly on fibroblasts. Tubular epithelial cells are the main site of p38 activation in the obstructed kidney. Angiotensin II and H₂O₂, but not IL-1 or lipopolysaccharide, induced p38 activation and upregulation of transforming growth factor-β₁, platelet-derived growth factor-B, and monocyte chemoattractant protein-1 production was suppressed in Ask1(-/-) tubular epithelial cells. In addition, macrophage accumulation was significantly inhibited in Ask1(-/-) UUO mice. In conclusion, ASK1 is an important upstream activator of p38 and JNK signaling in the obstructed kidney, and ASK1 is a potential therapeutic target in renal fibrosis.
authors.affiliation: Department of Nephrology and Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia.
authors.forename: Frank Y
authors.initials: FY
authors.lastname: Ma
authors.affiliation: Department of Nephrology and Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia.
authors.forename: Greg H
authors.initials: GH
authors.lastname: Tesch
authors.affiliation: Department of Nephrology and Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia david.nikolic-paterson@monash.edu.
authors.forename: David J
authors.initials: DJ
authors.lastname: Nikolic-Paterson
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000473:pathology*; D005355:Fibrosis; D007674:Kidney Diseases / Q000209:etiology / Q000473:pathology*; D007684:Kidney Tubules / Q000166:cytology / Q000473:pathology*; D048848:MAP Kinase Kinase Kinase 5 / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D061251:Primary Cell Culture; D015398:Signal Transduction / Q000502:physiology; D014517:Ureteral Obstruction / Q000150:complications / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*
chemical_list: D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse
keywords: apoptosis; apoptosis signal-regulating kinase 1; c-Jun NH2-terminal kinase; fibroblast; p38 mitogen-activated protein kinase