title: Fluorofenidone inhibits nicotinamide adeninedinucleotide phosphate oxidase via PI3K/Akt pathway in the pathogenesis of renal interstitial fibrosis.
abstract: OBJECTIVE
  Oxidative stress plays an important role in the progression of renal interstitial fibrosis. The nicotinamide adeninedinucleotide phosphate (NADPH) oxidase (Nox) family is considered one of the major sources of reactive oxygen species (ROS). In the present study, we investigated the inhibitory effects of a novel anti-fibrotic agent, Fluorofenidone (AKF-PD), upon Nox-mediated oxidative stress and deposition of extracellular matrix (ECM) in the development of renalinterstitial fibrosis.
  
  
  METHODS
  AKF-PD was used to treat renal fibrosis in unilateral ureteral obstruction (UUO) obstructive nephropathy in rats. The expression of Nox homologues, p-Akt, collagen I and III were detected by immunoblotting or immunohistochemistry. Levels of 8-iso prostaglandin F2alpha (8-Iso PGF2a) was measured by enzyme linked immunosorbent assay. In addition, ROS and the expression of collagen I (1a), Nox subunits and p-Akt was measured in angiotensin (Ang) II-stimulated rat proximal tubular epithelial (NRK-52E) cells in culture.
  
  
  RESULTS
  AKF-PD treatment significantly attenuated tubulo-interstitial injury, ECM deposition and oxidative stress in fibrotic rat kidneys. In addition, AKF-PD inhibited the expression of ROS, Collagen I (1a), Nox2, p-Akt in Ang II-stimulated NRK-52E cells.
  
  
  CONCLUSIONS
  AKF-PD attenuates the progression of renal interstitial fibrosis partly by suppressing NADPH oxidase and ECM deposition via the PI3K/Akt signalling pathway, suggesting AKF-PD is a potential novel therapeutic agent against renal fibrosis.
authors.affiliation: Division of Nephropathy, Department of Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Jiao
authors.initials: J
authors.lastname: Qin
authors.forename: Yan-Yun
authors.initials: YY
authors.lastname: Xie
authors.forename: Ling
authors.initials: L
authors.lastname: Huang
authors.forename: Qiong-Jing
authors.initials: QJ
authors.lastname: Yuan
authors.forename: Wen-Juan
authors.initials: WJ
authors.lastname: Mei
authors.forename: Xiang-Ning
authors.initials: XN
authors.lastname: Yuan
authors.forename: Gao-Yun
authors.initials: GY
authors.lastname: Hu
authors.forename: Guang-Jie
authors.initials: GJ
authors.lastname: Cheng
authors.forename: Li-Jian
authors.initials: LJ
authors.lastname: Tao
authors.forename: Zhang-Zhe
authors.initials: ZZ
authors.lastname: Peng
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002460:Cell Line; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism*; D024042:Collagen Type I / Q000378:metabolism; D015237:Dinoprost / Q000031:analogs & derivatives / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005355:Fibrosis; D007674:Kidney Diseases / Q000201:enzymology / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D007684:Kidney Tubules / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D015227:Lipid Peroxidation / Q000187:drug effects; D019808:Losartan / Q000494:pharmacology; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011728:Pyridones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D014162:Transfection; D014517:Ureteral Obstruction / Q000150:complications
chemical_list: C511655:5-methyl-1-(3-fluorophenyl)-2-(1H)-pyridone; D000975:Antioxidants; D024042:Collagen Type I; D004791:Enzyme Inhibitors; D008562:Membrane Glycoproteins; D011728:Pyridones; D000804:Angiotensin II; C075750:8-epi-prostaglandin F2alpha; D015237:Dinoprost; C500593:Cybb protein, rat; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D058543:Class Ia Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D019808:Losartan
keywords: Akt; fluorofenidone; nicotinamide adeninedinucleotide phosphate oxidase; renal interstitial fibrosis