Yu-Si Cheng1,2, Jie Chao2, Chen Chen3, Lin-Li Lv1, Yu-Chen Han1, Bi-Cheng Liu1. 1. Institute of Nephrology, School of Medicine, Southeast University, Nanjing, China. 2. Department of Physiology, School of Medicine, Southeast University, Nanjing, China. 3. Functional Experimental Laboratory, School of Medicine, Southeast University, Nanjing, China.
Abstract
OBJECTIVES: Oxidative stress plays a critical role in the pathogenesis of diabetic nephropathy (DN). p66shc is closely related to oxidative stress. However, the exact mechanism of its involvement in diabetic nephropathy is poorly understood. This study aimed to investigate the role of the p66shc-related pathway in diabetic nephropathy. METHODS: In an in-vivo experiment, rats were injected with streptozotocin to induce early diabetic nephropathy. The treatment groups were an aminoguanidine group and an enzastaurin group. In an in-vitro experiment, human renal proximal tubule epithelial cells (HK-2 cells) were cultured and incubated with high glucose. KEY FINDINGS: Upregulated protein expression of p66shc and p-p66shc was found in vivo and in vitro when cells were stimulated by high levels of glucose; this effect was accompanied by enhanced oxidative stress and damaged renal function, both of which were alleviated by p66shc siRNA. p66shc regulated NADPH oxidase, further promoting activation of oxidative stress. As an inhibitor of PKCβ, enzastaurin reduced the abnormal expression of p66shc and NADPH oxidase and alleviated renal injury. CONCLUSIONS: This study demonstrated enzastaurin alleviated diabetic renal injury via modulation of the PKCβ-p66shc-NADPH oxidase pathway, which provided a new perspective for the treatment of early DN.
OBJECTIVES: Oxidative stress plays a critical role in the pathogenesis of diabetic nephropathy (DN). p66shc is closely related to oxidative stress. However, the exact mechanism of its involvement in diabetic nephropathy is poorly understood. This study aimed to investigate the role of the p66shc-related pathway in diabetic nephropathy. METHODS: In an in-vivo experiment, rats were injected with streptozotocin to induce early diabetic nephropathy. The treatment groups were an aminoguanidine group and an enzastaurin group. In an in-vitro experiment, human renal proximal tubule epithelial cells (HK-2 cells) were cultured and incubated with high glucose. KEY FINDINGS: Upregulated protein expression of p66shc and p-p66shc was found in vivo and in vitro when cells were stimulated by high levels of glucose; this effect was accompanied by enhanced oxidative stress and damaged renal function, both of which were alleviated by p66shc siRNA. p66shc regulated NADPH oxidase, further promoting activation of oxidative stress. As an inhibitor of PKCβ, enzastaurin reduced the abnormal expression of p66shc and NADPH oxidase and alleviated renal injury. CONCLUSIONS: This study demonstrated enzastaurin alleviated diabetic renal injury via modulation of the PKCβ-p66shc-NADPH oxidase pathway, which provided a new perspective for the treatment of early DN.
Authors: Sergiy A Starosyla; Galyna P Volynets; Mykola V Protopopov; Volodymyr G Bdzhola; Denis O Pashevin; Valentyna O Polishchuk; Taisiia O Kozak; Dmytro O Stroi; Victor E Dosenko; Sergiy M Yarmoluk Journal: Struct Chem Date: 2022-10-11 Impact factor: 1.795