ERK5 activation enhances mesangial cell viability and collagen matrix accumulation in rat progressive glomerulonephritis

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.

Role of TGF-β in chronic kidney disease: an integration of tubular, glomerular and vascular effects

“…Furthermore, the transfection of ERK5-specific small interfering RNA results in a significant decrease in ANG-II-induced soluble collagen secretion (Urushihara et al 2010), thus suggesting that ERK5 also mediates the effect of TGF-β and Ang II on mesangial-derived ECM expansion. In addition, in human mesangial cells, mechanical stretch activates p38 MAP kinase, which independently induces TGF-β1 and fibronectin.…”

Protective Effects of Shichimotsu-koka-To on Irreversible Thy-1 Nephritis

“…Previous studies revealed that the overload of glomerular filtration increases cellular reactive oxygen species (ROS), and that ROS up-regulate cell proliferation and ECM expression in mesangial cells. 19,20) In this study, SKT suppressed both glomerular hypercellularity and ECM accumulation, together with recovery of tissue SOD-like activity, which is recognized as a ROS scavenger. Therefore, it is suspected that the antioxidative effect was one of the mechanisms of SKT treatment in the present study.…”

Renin-Angiotensin System Activation and Extracellular Signal-Regulated Kinases in Glomerulonephritis

“…MCs were serum-starved for 48 hours in serum-free RPMI 1640 medium, prior to stimulation with H 2 O 2 and/or Ang II in the presence or absence of reagents. Ang II-induced ERK5 phosphorylation in MCs was blocked by the pretreatment with ARB but not DPI, indicating that Ang II-induced ERK5 phosphorylation was mediated by the Ang II type 1 receptor and not by the Ang IIinduced NAD(P)H oxidase-dependent ROS production (Urushihara et al, 2010). Furthermore, the costimulation of MCs with Ang II and H 2 O 2 resulted in a synergistic increase in ERK5 phosphorylation, compared to the stimulation of MCs with either Ang II or H 2 O 2 (Urushihara et al, 2010).…”

“…Ang II-induced ERK5 phosphorylation in MCs was blocked by the pretreatment with ARB but not DPI, indicating that Ang II-induced ERK5 phosphorylation was mediated by the Ang II type 1 receptor and not by the Ang IIinduced NAD(P)H oxidase-dependent ROS production (Urushihara et al, 2010). Furthermore, the costimulation of MCs with Ang II and H 2 O 2 resulted in a synergistic increase in ERK5 phosphorylation, compared to the stimulation of MCs with either Ang II or H 2 O 2 (Urushihara et al, 2010). These findings suggest that Ang II directly induces ERK5 phosphorylation via NADPH in an oxidase-independent manner, and that ROS and Ang II could each induce ERK5 phosphorylation in MCs through different signaling pathways.…”