Piperazine ferulate ameliorates the development of diabetic nephropathy by regulating endothelial nitric oxide synthase

Abstract

Diabetic nephropathy (DN) is among the most common complications of diabetes mellitus. The disorder is associated with a decrease in the activity of the nitric oxide synthase/nitric oxide system. Piperazine ferulate (PF) is widely used for the treatment of kidney disease in China. The aim of the present study was to examine the effects of PF on streptozotocin (STZ)-induced DN and the underlying mechanism of this process. STZ-induced diabetic mice were intragastrically administered PF (100, 200 and 400 mg/kg/body weight/day) for 12 weeks. At the end of the treatment period, the parameters of 24-h albuminuria and blood urea nitrogen, creatinine and oxidative stress levels were measured. Hematoxylin and eosin staining, periodic acid-Schiff staining and electron microscopy were used to evaluate the histopathological alterations. mRNA and protein expression of endothelial nitric oxide synthase (eNOS) were measured by quantitative polymerase chain reaction and western blotting, respectively. PF significantly decreased blood urea nitrogen and creatinine levels and 24-h albuminuria, and it alleviated oxidative stress, improved glomerular basement membrane thickness and caused an upregulation in eNOS expression and activity levels in diabetic mice. In addition, high glucose decreased eNOS expression levels, whereas PF caused a reversal in the nitric oxide (NO) levels of glomerular endothelial cells. The present results suggested that PF exhibited renoprotective effects on DN. The mechanism of its action was associated with the regulation of eNOS expression and activity.

Piperazine ferulate attenuates high glucose‑induced mesangial cell injury via the regulation of p66Shc

“…A total of 45 mice were randomly divided into three groups (n=15 mice per group) as follows: A control group, a model group (DN) and the model + PF group (DN + PF group). Diabetic model mice were established according to a previously described protocol (24). PF was dissolved in 0.5% sodium carboxymethyl cellulose (CMC-Na).…”

“…Previous research has revealed that PF reduces the levels of blood urea nitrogen and serum creatinine in rats subjected to 5/6 nephrectomy (22) and exerts anti-hypertensive effects via the activation of endothelial nitric oxide synthase (eNOS) (23). Another previous study reported that PF administration can restore the HG-induced expression of eNOS in glomerular endothelial cells and delay the development of DN (24). However, it remains unknown as to whether PF restores mesangial cell injury under hyperglycemic conditions by inhibiting p66 Shc .…”

Roles of Endovascular Calyx Related Enzymes in Endothelial Dysfunction and Diabetic Vascular Complications

“…On the one hand, mitochondrial reactive oxygen species can lead to eNOS uncoupling, which in turn reduces NO bioavailability, increases the formation of peroxynitrite, causes vascular relaxation and cause cardiovascular disease (Cheang et al, 2014). Hyperglycemia can also cause eNOS uncoupling (Yang et al, 2019). NO can activate plasminogen activators and matrix metalloproteinases, inhibit interstitial collagen synthesis, and downregulate TGF-β and plasminogen activator inhibitor 1 (Goligorsky, 2017).…”

A review of endothelial nitric oxide synthase and diabetic nephropathy

“…程洁等人 [75] . Piperazine ferulate(PF)可上调肾小球内皮细胞eNOS表达 及活性, 降低血液肌酐及尿素氮水平, 保护肾脏并延缓 DN的发生 [2] . 维生素D可上调ET-1以及ET-B受体 mRNA表达以及eNOS mRNA表达, 进而使eNOS在 Swiss Webster鼠肾脏的表达增多 [78] , 这一结果证实了 ET与NO共同调节动脉血管张力, 维持血管稳态的重 要作用.…”

“…环境因素相互作用的严重代谢性疾病并发症 [1] , 是主 要的糖尿病(diabetes mellites, DM)微血管并发症之一, 是DM高致死率以及导致晚期肾病的的主要因素 [2] , 在全球透析疾病中占据了高达35%~40%的比率 [3] .…”