Fluorofenidone inhibits nicotinamide adeninedinucleotide phosphate oxidase via PI3K/Akt pathway in the pathogenesis of renal interstitial fibrosis.

Abstract

AIM:

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.

CONCLUSION:

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: Jiao Qin, Yan-Yun Xie, Ling Huang, Qiong-Jing Yuan, Wen-Juan Mei, Xiang-Ning Yuan, Gao-Yun Hu, Guang-Jie Cheng, Li-Jian Tao, Zhang-Zhe Peng
• Journal: Nephrology (Carlton, Vic.) (Nephrology (Carlton)) Vol. 18 Issue 10 Pg. 690-9 (Oct 2013) ISSN: 1440-1797 [Electronic] Australia
• PMID: 23841831 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 The Authors. Nephrology © 2013 Asian Pacific Society of Nephrology.

Chemical References

• 5-methyl-1-(3-fluorophenyl)-2-(1H)-pyridone
• Antioxidants
• Collagen Type I
• Enzyme Inhibitors
• Membrane Glycoproteins
• Pyridones
• Angiotensin II
• 8-epi-prostaglandin F2alpha
• Dinoprost
• Cybb protein, rat
• NADPH Oxidase 2
• NADPH Oxidases
• neutrophil cytosolic factor 1
• Class Ia Phosphatidylinositol 3-Kinase
• Proto-Oncogene Proteins c-akt
• Losartan

Topics

• Angiotensin II (pharmacology)
• Animals
• Antioxidants (pharmacology)
• Cell Line
• Class Ia Phosphatidylinositol 3-Kinase (genetics, metabolism)
• Collagen Type I (metabolism)
• Dinoprost (analogs & derivatives, metabolism)
• Disease Models, Animal
• Enzyme Inhibitors (pharmacology)
• Fibrosis
• Kidney Diseases (enzymology, etiology, pathology, prevention & control)
• Kidney Tubules (drug effects, enzymology, pathology)
• Lipid Peroxidation (drug effects)
• Losartan (pharmacology)
• Male
• Membrane Glycoproteins (antagonists & inhibitors, metabolism)
• NADPH Oxidase 2
• NADPH Oxidases (antagonists & inhibitors, metabolism)
• Oxidative Stress (drug effects)
• Phosphorylation
• Proto-Oncogene Proteins c-akt (metabolism)
• Pyridones (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Signal Transduction (drug effects)
• Transfection
• Ureteral Obstruction (complications)