A PPARγ agonist inhibits aldosterone-induced mesangial cell proliferation by blocking ROS-dependent EGFR intracellular signaling

Abstract

Mesangial cell (MC) proliferation is a key feature in the pathogenesis of a number of renal diseases. Peroxisome proliferator-activated receptor-␥ (PPAR␥) has attracted considerable attention for its effects on stimulating cell differentiation and on inducing cell cycle arrest. We previously showed that aldosterone (Aldo) stimulates MC proliferation via the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway, which was dependent on reactive oxygen species (ROS)-mediated epithelial growth factor receptor (EGFR) transactivation (Huang S, Zhang A, Ding G, and Chen R. Am J Physiol Renal Physiol 296: F1323-F1333, 2009). In this study, we examined whether the PPAR␥ agonist rosiglitazone inhibited Aldo-induced MC proliferation by modulating ROS-dependent EGFR intracellular signaling. Rosiglitazone at 1-10 M dose dependently inhibited Aldo-induced MC proliferation of cultured mouse MCs. The inhibitory effect was blocked by the PPAR␥ antagonist PD-68235, indicating that the rosiglitazone effect acted through PPAR␥ activation. Rosiglitazone also arrested Aldo-induced cell cycle progression and suppressed expression of cyclins D1 and A. Moreover, rosiglitazone dose dependently blocked Aldo-induced ROS production, EGFR phosphorylation, and PI3K/Akt activation. These results suggest that the PPAR␥ agonist rosiglitazone may inhibit Aldo-induced MC proliferation directly, by affecting ROS/EGFR/ PI3K/Akt signaling pathways and cell cycle-regulatory proteins. PPAR␥ might be a novel therapeutic target against glomerular diseases.peroxisome proliferator-activated receptor-␥; glomerular disease MESANGIAL CELLS (MCs) are resident cells of the glomerulus that are important for maintaining structure and function. Abnormal growth of glomerular MCs is a predominant histological feature of several glomerular diseases, and growth regulation may influence the outcome of glomerulonephritis (13,30,37). Elucidating the mechanisms of MC proliferation may contribute to the development of effective treatment strategies for glomerular diseases. However, the stimulation of MC proliferation in response to glomerular injury has been attributed to multiple factors, hindering our understanding of the molecular basis of this process (23,24,28,43).Recently, attention has focused on the role of aldosterone (Aldo) in the development and progression of cardiovascular disease and chronic kidney disease (1,14,16,38). As an important mediator of the renin-angiotensin-aldosterone system, plasma and tissue Aldo are elevated in diabetic and other Address for reprint requests and other correspondence:

Mitochondrial dysfunction in the pathophysiology of renal diseases

“…For example, they were able to reduce proteinuria and fibrotic responses and prevent podocyte as well as vascular injury, in both animal and clinical trials (87,121). Rosiglitazone, one of the TZDs, can effectively inhibit podocyte injury and MC proliferation through reduced ROS production and recovery of mitochondrial electron transport function in vivo and in vitro (65,154,160). TZDs also decrease TGF-␤ production in glomeruli, thus attenuating renal interstitial fibrosis (74).…”

Beyond Gap Junction Channel Function: the Expression of Cx43 Contributes to Aldosterone-Induced Mesangial Cell Proliferation via the ERK1/2 and PKC Pathways

“…Several studies have revealed that the renal mesangial cell (MC) is a target local of aldosterone (Aldo) action, where Aldo can induce glomerular injury characterized by mesangial matrix expansion and cell overgrowth through mineralcorticoid receptor (MR) activation [6][7][8], ROS generation, epithelial growth factor receptor (EGFR) phosphorylation, cell cycle-regulatory protein expression, and multiple signaling pathways [8][9][10]. However, the actual molecular mechanism responsible for Aldo-induced MC proliferation is far from clear.…”

“…Considering the presence of connexins within the kidney and their functional role in growth regulation [8,[11][12][13], analysis of connexins provides a new viewpoint for investigating CKD. Connexins are a multi-gene family of transmembrane proteins with ~20 isoforms.…”

EPA and DHA increased PPARγ expression and deceased integrin-linked kinase and integrin β1 expression in rat glomerular mesangial cells treated with lipopolysaccharide

“…A key finding is that PPARγ agonists, including troglitazone, rosiglitazone, and prostaglandin J2, significantly decrease the increased expression of TNFα and IL-6 (19). Rosiglitazone inhibits mesangial cell proliferation by blocking reactive oxygen species (ROS)-dependent epidermal growth factor receptor (EGFR) intracellular signaling, and telmisartan has powerful anti-infl ammatory action via PPARγ activation in mesangial cells (20). PPARγ may prove to be a pharmacological target for treatment of glomerulonephritis (19).…”