AKF-PD alleviates diabetic nephropathy via blocking the RAGE/AGEs/NOX and PKC/NOX Pathways

• Published in: Scientific reports 2019-03, Vol.9 (1), p.4407-4407, Article 4407
• Main Authors: Qin, Jiao, Peng, Zhangzhe, Yuan, QiongJing, Li, Qian, Peng, Yu, Wen, Rui, Hu, Zhaolan, Liu, Jun, Xia, Xiongfang, Deng, Hong, Xiong, Xuan, Hu, Jinyue, Tao, Lijian
• Format: Article
• Language: English
• Subjects: 13; 13/1; 13/21; 14; 38; 631/337/1644; 692/699/1585/3182; 82; 82/80; Advanced glycosylation end products; Animals; Blotting, Western; Cell Line; Diabetes; Diabetes mellitus; Diabetic Nephropathies - drug therapy; Diabetic Nephropathies - metabolism; Diabetic nephropathy; Glucose; Glutathione peroxidase; Glycation End Products, Advanced - metabolism; Glycosylation; Humanities and Social Sciences; Humans; Immunohistochemistry; Kinases; Male; Membrane Potential, Mitochondrial - drug effects; Membrane Potential, Mitochondrial - physiology; Mesangial cells; Mesangial Cells - drug effects; Mesangial Cells - metabolism; Mice; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; multidisciplinary; NAD(P)H oxidase; NADPH Oxidase 4 - metabolism; NADPH Oxidases - metabolism; NADPH-diaphorase; Nephropathy; NOX4 protein; Oxidative stress; Oxidative Stress - drug effects; Oxidative Stress - physiology; Pathogenesis; Protein kinase C; Protein Kinase C - metabolism; Pyridones - therapeutic use; Reactive oxygen species; Receptor for Advanced Glycation End Products - metabolism; Renal function; Reverse Transcriptase Polymerase Chain Reaction; Science; Science (multidisciplinary); Signal Transduction - drug effects; Superoxide dismutase; Therapeutic applications
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-018-36344-w

Diabetic nephropathy (DN) is a major complication of diabetes. Currently, drugs are not available to effectively control the disease. Fluorofenidone (AKF-PD) is a recently developed drug; it possesses activities in reducing DN progression in preclinical research. Nonetheless, its renal protection and the underlying mechanisms have not been thoroughly investigated. We report here that AKF-PD significantly alleviatesrenal oxidative stress (OS) in db / db mice through downregulation of Nicotinamide Adenine Dinucleotide Phosphate (NADPH) oxidase and upregulation of glutathione peroxidase and superoxide dismutase, thereby protecting kidney from DN pathogenesis. AKF-PD likely reduces OS through the advanced glycation end products (AGE) and protein kinase C (PKC) pathways. While renal AGEs, PKCα, PKCβ, and NADPH oxidase 4 (NOX4) were all substantially upregulated in db / db mice compared to db / m animals, AKF-PD robustly downregulated all these events to the basal levelsdetected in db / m mice. In primary human renal mesangial cells (HMCs), high glucose (HG) elevated receptor for advanced glycation endproducts (RAGE), PKCα, PKCβ and NOX4 activity, and induced the production of reactive oxygen species (ROS); these events were all inhibited by AKF-PD. Furthermore, HG led to mitochondrial damagein HMCs;AKF-PD conferred protection on the damage. Knockdown of either PKCα or PKCβ reduced HG-induced ROS production and mitochondrial damage in HMCs. The knockdown significantly enhanced AKF-PD-mediated inhibition of ROS production and mitochondrial damage in HG-treated HMCs. Collectively, our study demonstrates that AKF-PD protects renal function under diabetes conditions in part through inhibition of OS during DN pathogenesis. AKF-PD can be explored for clinical applications in DN therapy.