A PPARgamma agonist inhibits aldosterone-induced mesangial cell proliferation by blocking ROS-dependent EGFR intracellular signaling.
Mesangial cell (MC) proliferation is a key feature in the pathogenesis of a number of renal diseases. Peroxisome proliferator-activated receptor-γ (PPARγ) 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 PPARγ agonist rosiglitazone inhibited Aldo-induced MC proliferation by modulating ROS-dependent EGFR intracellular signaling. Rosiglitazone at 1-10 μM dose dependently inhibited Aldo-induced MC proliferation of cultured mouse MCs. The inhibitory effect was blocked by the PPARγ antagonist PD-68235, indicating that the rosiglitazone effect acted through PPARγ 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 PPARγ agonist rosiglitazone may inhibit Aldo-induced MC proliferation directly, by affecting ROS/EGFR/PI3K/Akt signaling pathways and cell cycle-regulatory proteins. PPARγ might be a novel therapeutic target against glomerular diseases.
Department of Nephrology, Nanjing Children's Hospital, Nanjing Medical University, Nanjing, Jiangsu Province,China.
Yanggang
Y
Yuan
Aihua
A
Zhang
Songming
S
Huang
Guixia
G
Ding
Ronghua
R
Chen
D000450:Aldosterone / Q000378:metabolism*; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D019925:Cyclin A / Q000037:antagonists & inhibitors; D019938:Cyclin D1 / Q000037:antagonists & inhibitors; D066246:ErbB Receptors / Q000378:metabolism*; D050527:Mesangial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D009574:Nitro Compounds / Q000494:pharmacology; D047495:PPAR gamma / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology*
D019925:Cyclin A; D000451:Mineralocorticoid Receptor Antagonists; D009574:Nitro Compounds; C430895:PD 068235; D047495:PPAR gamma; D017382:Reactive Oxygen Species; D013844:Thiazoles; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D019938:Cyclin D1; D000450:Aldosterone; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt