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ERK5 activation enhances mesangial cell viability and collagen matrix accumulation in rat progressive
Maki Urushihara1, Masanori Takamatsu, Maki Shimizu
1Department of Pediatrics, Institute of Health Bioscience, University of Tokushima Graduate School, Tokushima, Japan. murushih@tulane.edu
Abstract:
The mitogen-activated protein kinase (MAPK) cascade plays an important role in the regulation of various cellular functions in glomerulonephritis (GN). Here, we investigated whether extracellular signal-regulated kinase 5 (ERK5), a member of the MAPK family, is involved in the pathogenesis of chronic mesangioproliferative GN, using a rat model induced by uninephrectomy and anti-Thy-1 antibody injection. Immunostaining of kidneys obtained at different time points revealed that phospho-ERK5 was weakly expressed in control glomeruli but dramatically increased in a typical mesangial pattern after 28 and 56 days of GN. A semiquantitative assessment indicated that glomerular phospho-ERK5 expression closely paralleled the accumulation of extracellular matrix (ECM), collagen type I, as well as glomerular expression of reactive oxygen species (ROS) and ANG II. On the other hand, phospho-ERK1/2 expression increased on day 7 during the phase of enhanced mesangial cell (MC) proliferation and decreased thereafter. H(2)O(2) and ANG II each induced ERK5 phosphorylation by cultured rat MCs. Costimulation with both H(2)O(2) and ANG II synergistically increased ERK5 phosphorylation in MCs. Cultured MCs transfected with ERK5-specific small interference RNA showed a significant decrease in H(2)O(2) or ANG II-induced cell viability and soluble collagen secretion compared with control cells. Treatment of GN rats with an ANG II type 1 receptor blocker resulted in significant decreases in phospho-ERK5 expression and collagen accumulation accompanied by remarkable histological improvement. Taken together, these results suggest that MC ERK5 phosphorylation by ANG II or H(2)O(2) enhances cell viability and ECM accumulation in an experimental model of chronic GN.
Insights
Extracellular signal-regulated kinase 5 (ERK5) is implicated in chronic glomerulonephritis (GN). Blocking ANG II signaling reduces ERK5 activation, extracellular matrix accumulation, and improves kidney histology in a rat GN model.
Area of Science:
- Nephrology
- Cellular Biology
- Molecular Medicine
Background:
- The mitogen-activated protein kinase (MAPK) cascade regulates cellular functions relevant to glomerulonephritis (GN).
- The role of extracellular signal-regulated kinase 5 (ERK5) in chronic mesangioproliferative GN pathogenesis remains unclear.
Purpose of the Study:
- To investigate the involvement of ERK5 in the pathogenesis of chronic mesangioproliferative GN.
- To elucidate the mechanisms by which ERK5 contributes to extracellular matrix accumulation in GN.
Main Methods:
- Utilized a rat model of chronic GN induced by uninephrectomy and anti-Thy-1 antibody injection.
- Performed immunostaining, semiquantitative assessment, and cell culture experiments with rat mesangial cells (MCs).
- Assessed the effects of angiotensin II (ANG II) and hydrogen peroxide (H2O2) on ERK5 phosphorylation and MC function, and evaluated the impact of an ANG II receptor blocker.
Main Results:
- Glomerular phospho-ERK5 expression significantly increased in GN rats, correlating with extracellular matrix (ECM) accumulation, collagen type I, reactive oxygen species (ROS), and ANG II levels.
- ERK5 phosphorylation in cultured rat MCs was induced by H2O2 and ANG II, with synergistic effects upon co-stimulation.
- ERK5 knockdown in MCs reduced cell viability and soluble collagen secretion induced by H2O2 or ANG II.
- ANG II type 1 receptor blockade in GN rats decreased phospho-ERK5, collagen accumulation, and improved kidney histology.
Conclusions:
- ERK5 phosphorylation, induced by ANG II or H2O2 in mesangial cells, contributes to cell viability and ECM accumulation in experimental chronic GN.
- ERK5 represents a potential therapeutic target for managing chronic mesangioproliferative GN.
