| First Author | Qin J | Year | 2019 |
| Journal | Sci Rep | Volume | 9 |
| Issue | 1 | Pages | 4407 |
| PubMed ID | 30867431 | Mgi Jnum | J:276854 |
| Mgi Id | MGI:6307385 | Doi | 10.1038/s41598-018-36344-w |
| Citation | Qin J, et al. (2019) AKF-PD alleviates diabetic nephropathy via blocking the RAGE/AGEs/NOX and PKC/NOX Pathways. Sci Rep 9(1):4407 |
| abstractText | 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/dbmice 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, PKCalpha, PKCbeta, 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), PKCalpha, PKCbeta 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 PKCalpha or PKCbeta 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. |
