Differential regulation of angiotensin II‐induced extracellular signal regulated kinase‐1/2 and ‐5 in progressive glomerulonephritis

AbstractAimExtracellular 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.MethodsA 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).ResultsRats 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.ConclusionAltogether, these data suggest that ERK1/2 regulates acute inflammatory reactions, while ERK5 promotes the development of RAS‐induced chronic glomerular fibrosis activation in GN.