title: Differential regulation of angiotensin II-induced extracellular signal regulated kinase-1/2 and -5 in progressive glomerulonephritis.
abstract: OBJECTIVE
  Extracellular signal regulated kinase (ERK)1/2 and ERK5 are key kinases of the signalling pathways involved in various cellular responses to kidney injury; however, the mechanistic links between those kinase and renin-angiotensin system (RAS) activations in glomerulonephritis (GN) have not been fully elucidated. In this study, we sought to clarify the potential roles of ERK1/2 and ERK5 via RAS activation in the pathogenesis of GN.
  
  
  METHODS
  A rat model of progressive GN was induced by anti-glomerular basement membrane (GBM) injection and the signal transduction pathway in angiotensin II (Ang II)-induced glomerular pathologic alterations were investigated in primary cultured mesangial cells (MCs).
  
  
  RESULTS
  Rats developed typical cellular crescents in glomeruli on day 7 that progressed to severe fibrocellular crescents and glomerulosclerosis on day 28. Strong expression of phospho-ERK1/2 was observed on day 7 and phospho-ERK5 expression was markedly increased on day 28 of GN. An angiotensin II type 1 receptor blocker (ARB) suppressed those augmentations. Moreover, ARB treatment attenuated the increases in macrophage infiltration and PCNA-positive cells observed on day 7 in GN rats, as well as the increase in collagen type 1 expression on day 28. Consistently, MCs stimulated by Ang II showed significant increases in proliferation and the expression of MCP-1 and collagen type 1. Interestingly, while the ERK1/2 inhibitor PD98059 abolished the elevations in MCP-1 expression and cell proliferation, the ERK5 inhibitor BIX02189 abrogated the elevation in collagen type 1 expression.
  
  
  CONCLUSIONS
  Altogether, these data suggest that ERK1/2 regulates acute inflammatory reactions, while ERK5 promotes the development of RAS-induced chronic glomerular fibrosis activation in GN.
authors.affiliation: Department of Pediatrics, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nagai
authors.affiliation: Department of Pediatrics, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan. urushihara@tokushima-u.ac.jp.
authors.forename: Maki
authors.initials: M
authors.lastname: Urushihara
authors.affiliation: Department of Pediatrics, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Kinoshita
authors.affiliation: Department of Pediatrics, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
authors.forename: Ariunbold
authors.initials: A
authors.lastname: Jamba
authors.affiliation: Department of Pediatrics, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Kondo
authors.affiliation: Department of Pediatrics, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Kagami
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D004195:Disease Models, Animal; D005355:Fibrosis / Q000378:metabolism; D005920:Glomerular Mesangium / Q000378:metabolism* / Q000473:pathology; D005921:Glomerulonephritis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007249:Inflammation / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D051381:Rats; D012084:Renin-Angiotensin System / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000804:Angiotensin II; D048052:Mitogen-Activated Protein Kinase 3
keywords: extracellular signal-regulated kinase; fibrosis; glomerulonephritis; macrophage infiltration; renin-angiotensin system