title: Estrogen-related receptor (ERR) γ protects against puromycin aminonucleoside-induced podocyte apoptosis by targeting PI3K/Akt signaling.
abstract: Accumulating evidence has shown that podocyte apoptosis is of vital importance for the development of glomerulosclerosis and progressive loss of renal function. However, the molecular mechanisms leading to podocyte apoptosis are still elusive. In this study, we investigated the role of estrogen-related receptor (ERR) γ in podocyte apoptosis, as well as the underlying mechanisms. Treatment of PAN caused a dose- and time-dependent podocyte apoptosis in line with a significant downregulation of ERRγ. Interestingly, the occurrence of ERRγ downregulation appeared earlier than the onset of cell apoptosis, suggesting a potential that ERRγ reduction triggered apoptotic response in podocyte. To test this hypothesis, ERRγ siRNA was administered to the podocytes. Strikingly, ERRγ silencing resulted in a significant cell apoptosis accompanied with increased injury markers of B7-1 and cathepsin L and decreased podocyte protein nephrin. In contrast, overexpression of ERRγ remarkably attenuated PAN-induced cell apoptosis. Moreover, ERRγ overexpression stimulated PI3K/Akt signaling pathway evidenced by increased expression of PI3K subunits p85α and p110α and phosphorylated Akt. Importantly, a specific PI3K inhibitor LY294002 entirely reversed the anti-apoptotic effect of ERRγ following PAN treatment. Finally, we observed a striking downregulation of ERRγ in PAN-treated rat kidneys, suggesting that our cell model replicated the in vivo condition. Taken together, these data highly suggested that ERRγ played a novel role in modulating podocyte apoptosis by targeting PI3K/Akt signaling pathway.
authors.affiliation: Department of Nephrology, Nanjing Children's Hospital Affiliated to Nanjing Medical University, Nanjing 210008, China; State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Gong
authors.affiliation: Department of Nephrology, Nanjing Children's Hospital Affiliated to Nanjing Medical University, Nanjing 210008, China; State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Nephrology, Nanjing Children's Hospital Affiliated to Nanjing Medical University, Nanjing 210008, China; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Qilei
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Nephrology, Nanjing Children's Hospital Affiliated to Nanjing Medical University, Nanjing 210008, China; Nanjing Key Laboratory of Pediatrics, Nanjing 210008, China.
authors.forename: Shuzhen
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Nephrology, Nanjing Children's Hospital Affiliated to Nanjing Medical University, Nanjing 210008, China; State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Jiayu
authors.initials: J
authors.lastname: Song
authors.affiliation: Department of Nephrology, Nanjing Children's Hospital Affiliated to Nanjing Medical University, Nanjing 210008, China; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing 210029, China; Nanjing Key Laboratory of Pediatrics, Nanjing 210008, China.
authors.forename: Zhanjun
authors.initials: Z
authors.lastname: Jia
authors.affiliation: Department of Nephrology, Nanjing Children's Hospital Affiliated to Nanjing Medical University, Nanjing 210008, China; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing 210029, China; Nanjing Key Laboratory of Pediatrics, Nanjing 210008, China.
authors.forename: Songming
authors.initials: S
authors.lastname: Huang
authors.affiliation: Department of Nephrology, Nanjing Children's Hospital Affiliated to Nanjing Medical University, Nanjing 210008, China; State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing 210029, China; Nanjing Key Laboratory of Pediatrics, Nanjing 210008, China. Electronic address: zhaihua@njmu.edu.cn.
authors.forename: Aihua
authors.initials: A
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects; D008297:Male; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D050199:Podocytes / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D011692:Puromycin Aminonucleoside / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: C493778:Esrrg protein, rat; D011960:Receptors, Estrogen; D011692:Puromycin Aminonucleoside; D019869:Phosphatidylinositol 3-Kinases
keywords: Apoptosis; ERRγ; PI3K/Akt; Podocyte