Abstract
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, 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.
Highlights
The pathogenesis of Diabetic nephropathy (DN) is associated with oxidative stress (OS), renal hemodynamic dysfunction, micro-inflammatory reaction, metabolic disorders, the production of multiple cytokines and vasoactive molecules like angiotensin II and endothelin, and mesangial cell proliferation as well as extracellular matrix (ECM) accumulation[4,5,6,7,8]
It is known that the advanced glycation end products (AGEs) and the protein kinase C (PKC) signal pathway play a central role in the expression of Nicotinamide Adenine Dinucleotide Phosphate (NADPH) oxidase/OS29, which might be the targets of AKF-PD in DN treatment
Evidence suggests that AKF-PD is better than losartan indeceasing urine protein at 8 weeks (p < 0.05), at the same time we confirmed that AKF-PD did not influence uric acid and serum serum creatinine in AKF-PD treated mice compared to db/db mice
Summary
The pathogenesis of DN is associated with OS, renal hemodynamic dysfunction, micro-inflammatory reaction, metabolic disorders, the production of multiple cytokines and vasoactive molecules like angiotensin II and endothelin, and mesangial cell proliferation as well as ECM accumulation[4,5,6,7,8]. Plenty preclinical experiments have been conducted to examine the anti-fibrosis pharmacology of numerous drugs, including statins, rhubard and tripterygium, poricoic acid, ergone and so on[4,5,6,7,13,14,15,16,17] These drugs display activities in regulating cytokines secretion and reducing inflammatory reactions; their safety and clinical efficacy are under investigation. ROS promotes DN initiation and progression by affecting multiple DN processes These properties indicate targeting ROS being attractive in DN therapy. We aimed to detect the therapeutic effects of AKF-PD in DN and to explore the related molecular mechanism both in vitro and in vivo
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
