Abstract
Diabetic nephropathy (DN) is one of the most severe complications of diabetes mellitus. This study aimed to determine the effects and potential mechanism of caffeic acid para-nitro phenethyl ester (CAPE-pNO2), a derivative of caffeic acid phenethyl ester (CAPE), on DN; In vivo, intraperitoneal injections of streptozotocin (STZ) were used to induce diabetes in mice; then, the mice were intraperitoneally injected daily with CAPE or CAPE-pNO2 for 8 weeks. The mice were sacrificed, and blood samples and kidney tissues were collected to measure biological indexes. The results showed that CAPE and CAPE-pNO2 could lower serum creatinine, blood urea nitrogen, 24-h albumin excretion, malondialdehyde and myeloperoxidase levels and increase superoxide dismutase activity in diabetic mice. According to HE, PAS and Masson staining, these two compounds ameliorated structural changes and fibrosis in the kidneys. In addition, the immunohistochemical and western blot results showed that CAPE and CAPE-pNO2 inhibited inflammation through the Akt/NF-κB pathway and prevented renal fibrosis through the TGF-β/Smad pathway. In vitro, CAPE and CAPE-pNO2 inhibited glomerular mesangial cell (GMC) proliferation, arrested cell cycle progression and suppressed ROS generation. These compounds also inhibited ECM accumulation via regulating the TGF-β1, which was a similar effect to that of the NF-κB inhibitor PDTC. More importantly, CAPE and CAPE-pNO2 could up-regulate nitric oxide synthase expression in STZ-induced diabetic mice and HG-induced GMCs. CAPE-pNO2 had stronger effects than CAPE both in vivo and in vitro. These data suggest that CAPE-pNO2 ameliorated DN by suppressing oxidative stress, inflammation, and fibrosis via the Akt/NF-κB/ iNOS pathway.
Highlights
Diabetic nephropathy (DN) is one of the major microvascular complications of diabetes and could be a common cause of chronic kidney disease (CKD) [1]
It has been reported that DN may lead to end-stage renal disease (ESRD) in both type 1 and type 2 diabetes mellitus; ESRD is becoming the most prevalent cause of morbidity and complications due to diabetes, and it is characterized by glomerular extracellular matrix (ECM) deposition, glomerular basement membrane thickening, glomerular mesangial cell (GMC) proliferation and metabolic abnormalities [2,3,4,5]
Fasting blood glucose (FBG) levels were significant decreased after treatment with caffeic acid phenethyl ester (CAPE) or CAPE-pNO2 (p < 0.05), whereas the kidney-to-body weight ratios were significantly different in the high CAPE-pNO2 group only (p < 0.05)
Summary
Diabetic nephropathy (DN) is one of the major microvascular complications of diabetes and could be a common cause of chronic kidney disease (CKD) [1]. Oxidative stress is regarded as one of the major causes of the pathogenesis of DN, and oxidative stress caused by a chronic increase in reactive oxygen species (ROS) levels plays a pivotal role in kidney disease [7]. ROS generation can directly trigger a variety of stress-sensitive pathways and activate various downstream elements; and inflammation is a major response mediated by oxidative stress [11,12]. Activated NF-κB can be transferred to the nucleus and induce the expression of its downstream target gene TGF-β1 to cause ECM accumulation, which leads to fibrosis in DN [19]
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