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.
Filtration barrier injury induced by high glucose (HG) levels leads to the development of diabetic nephropathy. The endothelial glycocalyx plays a critical role in glomerular barrier function. In the present study, the effects of piperazine ferulate (PF) on HG-induced filtration barrier injury of glomerular endothelial cells (GEnCs) were investigated and the underlying mechanism was assessed. Immunofluorescence was used to observe the distribution of the glycocalyx as well as the expression levels of syndecan-1 and Zonula occludens-1 (ZO-1). Endothelial permeability assays were performed to assess the effects of PF on the integrity of the filtration barrier. Protein and mRNA expression levels were measured by western blotting and reverse transcription-quantitative PCR analyses, respectively. In vitro experiments revealed that adenosine monophosphate-activated protein kinase (AMPK) mediated HG-induced glycocalyx degradation and endothelial barrier injury. PF inhibited the HG-induced endothelial barrier injury and restored the expression levels of heparanase-1 (Hpa-1), ZO-1 and occludin-1 by AMPK. In vivo assays demonstrated that PF reduced the expression levels of Hpa-1, increased the expression levels of ZO-1 and attenuated glycocalyx degradation in the glomerulus. These data suggested that PF attenuated HG-induced filtration barrier injury of GEnC by regulating AMPK expression.
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