Abnormal and excessive growth of mesangial cells is important in the pathophysiologic processes of diabetes-associated interstitial fibrosis and glomerulosclerosis, leading to diabetic nephropathy, which eventually turns into end-stage renal disease. Sauchinone, a biologically-active lignan isolated from aerial parts of Saururus chinensis, has anti-inflammatory and anti-viral activities effects on various cell types. However, there are no studies reporting the effects of sauchinone on diabetic nephropathy. The present study aims to investigate the role of sauchinone in mesangial cell proliferation and fibrosis induced by angiotensin II, as well as the underlying mechanisms of these processes. Human renal mesangial cells were induced by angiotensin II (AngII, 10 μM) in the presence or absence of sauchinone (0.1–1 μM) and incubated for 48 h. In this study, we found that AngII induced mesangial cell proliferation, while treatment with sauchinone inhibited the cell proliferation in a dose-dependent manner. Pre-treatment with sauchinone induced down-regulation of cyclins/CDKs and up-regulation of CDK inhibitor, p21, and p27kip1 expression. In addition, AngII-enhanced expression of fibrosis biomarkers such as fibronectin, collagen IV, and connective tissue growth factor (CTGF), which was markedly attenuated by sauchinone. Sauchinone also decreased AngII-induced TGF-β1 and Smad-2, Smad-3, and Smad-4 expression. This study further revealed that sauchinone ameliorated AngII-induced mesangial inflammation through disturbing activation of inflammatory factors, and NLRP3 inflammasome, which is composed of the NLRP3 protein, procaspase-1, and apoptosis-associated speck-like protein containing a CARD (ASC). Moreover, pretreatment of sauchinone inhibited NF-κB translocation and ROS production in AngII-exposed mesangial cells. These data suggest that sauchinone has a protective effect on renal proliferation, fibrosis and inflammation. Therefore, sauchinone might be a potential pharmacological agent in prevention of AngII-induced renal damage leading to diabetic nephropathy.
Atherosclerosis is a chronic vascular disease and characterized by accumulation within the intima of inflammatory cells, smooth muscle cells, lipid, and connective tissue. Here, we suggest securinine as an anti‐atherosclerotic agent to attenuate vascular dysfunction and lesion. To identify natural agents that commonly reverse advanced atherosclerotic plaque to early atherosclerotic plaque, significantly regulated genes were analyzed in silico. The differentially expressed genes from 9 intimal thickening and 8 fibrous cap atheroma tissue which were collected from GEO data were assessed by the connectivity map. Natural candidate securinine, a main compound from Securinega suffruticosa, was selected and administrated 1, 5 mg/kg/day in apolipoprotein‐E‐deficient (ApoE KO) mice for 18 weeks. Securinine significantly showed lowered blood pressure and improvement of metabolic parameters with hyperlipidemia. The impairment in vasorelaxation was remarkably decreased by treatment with securinine. H&E staining revealed that treatment with securinine reduced atherosclerotic lesions. Securinine suppressed the expression of adhesion molecules and matrix metalloproteinase‐2/‐9 in both ApoE KO and vascular endothelial cells (HUVEC). In HUVEC pretreatment with securinine significantly inhibited ROS generation and NF‐κB activation. Growth curve assays using the real‐time cell analyzer showed that securinine significantly decreased TNF‐α‐induced aortic smooth muscle cell proliferation and migration in a dose‐dependent manner. Thus securinine may be a potential natural candidate for the treatment of atherosclerosis because it attenuates vascular inflammation and dysfunction as well as vascular lesion. Support or Funding Information This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (2017R1A5A2015805)(2017R1D1A3B03029089) (2019R1A2C1085650).
Mesangial proliferative glomerulonephritis is characterized by an increased number of mesangial cells in the glomeruli in the kidneys and damage to the glomeruli by activation of some growth factors (e.g., angiotensin II) and deposition of extracellular matrix proteins. However, the effect of sauchinone on mesangial proliferative glomerulonephritis is still unclear. In the present study, we investigated the protective effect of sauchinone against angiotensin II (AngII)‐induced proliferation and fibrosis in human renal mesangial cells. Thus, this study was investigated the inhibitory effect of sauchinone (0.1–1 μM) on AngII‐stimulated mesangial cells proliferation and fibrosis. Sauchinone, one of the active lignan isolated from Saururus chinensis, was reported to possess broad bioactivities, such as anti‐inflammatory, anti‐oxidant, anti‐tumor, anti‐apoptosis and anti‐obesity effects. In this study, thymidine incorporation under AngII was significantly accelerated, which was inhibited by sauchinone in a dose dependent manner. In migration assays, a significant reduction in wound surface was observed in pretreatment of sauchinone. Sauchinone induced down‐regulation of cyclins/CDKs and up‐regulation of CDK inhibitor, p21waf1/cip1 and p27kip1 expression. In addition, AngII enhanced expression of fibrosis biomarkers such as collagen IV and CTGF, which was markedly attenuated by sauchinone. Sauchinone decreased TGF‐β1 and Smad‐2/Smad‐4 expression, whereas increased Smad‐7 expression under AngII. Furthermore, sauchinone inhibited AngII‐induced inflammatory factors level as well as NF‐κB p65 translocation and ROS production. These results suggested that sauchinone may alleviate mesangial proliferation and inflammation possibly involved in renal fibrotic process, further mesangial proliferative glomerulonephritis through disturbing TGF‐β1/Smad signaling and NLRP3 inflammasome pathway. Thus, sauchinone might prove to be effective in the treatment of renal dysfunction leading to mesangial proliferative glomerulonephritis. Support or Funding Information This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (2017R1A5A2015805)(2018R1D1A1B07050720).
Renal ischemia-reperfusion (I/R) injury is an important cause of acute renal failure (ARF). Geumgwe-sinkihwan (GSH) was recorded in a traditional Chines medical book named “Bangyakhappyeon” in 1884. GSH has been used for treatment for patients with diabetes and glomerulonephritis caused by deficiency of kidney yang and insufficiency of kidney gi. Here we investigate the effects of GSH in mice model of ischemic acute kidney injury. The mice groups are as follows; sham group: C57BL6 male mice, I/R group: C57BL6 male mice with I/R surgery, GSH low group: I/R + 100 mg/kg/day GSH, and GSH high group: I/R + 300 mg/kg/day GSH. Ischemia was induced by clamping both renal arteries and reperfusion. Mice were orally given GSH (100 and 300 mg/kg/day) during 3 days after surgery. Treatment with GSH significantly ameliorated creatinine clearance, creatinine, and blood urea nitrogen levels. Treatment with GSH reduced neutrophil gelatinase associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1), specific renal injury markers. GSH also reduced the periodic acid–Schiff and picro sirius red staining intensity in kidney of I/R group. Western blot and real-time RT-qPCR analysis demonstrated that GSH decreased protein and mRNA expression levels of the inflammatory cytokines in I/R-induced ARF mice. Moreover, GSH inhibited protein and mRNA expression of inflammasome-related protein including NLRP3 (NOD-like receptor pyrin domain-containing protein 3, cryoprin), ASC (Apoptosis-associated speck-like protein containing a CARD), and caspase-1. These findings provided evidence that GSH ameliorates renal injury including metabolic dysfunction and inflammation via the inhibition of NLRP3-dependent inflammasome in I/R-induced ARF mice.
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