Long-chain bases from sea cucumber inhibits renal fibrosis and apoptosis in type 2 diabetic mice
Introduction
Type 2 diabetes mellitus is a worldwide epidemic associated with high morbidity. More than 90% of diabetic patients belong to type 2 diabetes, and it is predicted that worldwide diabetes prevalence will reach up to 550 million by 2030 (Shaw et al., 2010, Yoon et al., 2006). Diabetic nephropathy (DN) is one of the most common and serious complications of type 2 diabetes mellitus at a ratio of approximately 40% (Wang, Zhao, Yang, Wang, & Kuang, 2016). Furthermore, DN is the leading cause of significant mortality in type 2 diabetic patients, as 30%-45% of the patients eventually develop end-stage renal disease (ESRD) (Pan et al., 2014, Rhee et al., 2017). It is characterized by excessive extracellular matrix (ECM) with glomerular and tubular basement membrane (GBM) thickening, tubulointerstitial fibrosis, and renal inflammation, resulting in severe nephropathy appearance such as a slowly increasing proteinuria and a gradually decreasing renal function. Renal fibrosis is a final common pathologic feature in the later stage of disease. Transforming growth factor β (TGF-β)/Smad signaling-mediated ECM accumulation, including fibronection, directly induces fibrotic lesions (Lan & Chung, 2012). Therefore, inhibition of TGF-β/Smad pathway has become a promising therapeutic candidate for precaution of DN. Significant apoptosis occurs in the glomeruli and renal tubules from the early stage of nephropathy to especially ESRD (Verzola et al., 2007). Renal apoptosis is a hallmark of DN and a reliable indicator of the disease progression (Brezniceanu et al., 2010). Phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB/Akt) signaling is proved to be widely expressed in eukaryotes and plays essential roles in growth, differentiation, proliferation and survival (Cantley, 2002). Meanwhile, PI3K/Akt pathway is also involved in renal apoptosis of type 2 diabetic mice (Huang et al., 2016). Mitogen-activated protein kinase (MAPK) pathway is another important pathological mechanism of renal apoptosis. Extracellular signal-regulated kinase 1/2 (ERK1/2) is one of the crucial kinase in MAPK family, and phosphorylated ERK1/2 triggered inactivation of caspase 3 through regulation of Bax and Bcl-2 (You et al., 2017).
Increasing attentions have been attracted in the paper on long-chain bases (LCBs), also namely sphingoid bases, the simplest members in the family glycosphingolipids. Current research has proved that LCBs exerted several bioactivities, such as regulation of apoptotic-like programmed cell death in plants (Alden et al., 2011), synergistic antioxidant activity with α-tocopherol (Shimajiri, Shiota, Hosokawa, & Miyashita, 2013), improvement in type 2 diabetes (Wei et al., 2014), and inhibition of keratinocyte differentiation (Sigruener et al., 2013). Due to the special environment, LCBs from marine organism exhibit better bioactivities (Bordbar, Anwar, & Saari, 2011). Therefore, significant studies were carried out on LCBs extracted from sea cucumbers (SC-LCBs), the popular traditional marine foods in China. SC-LCBs exhibited stronger inhibitory effect on cell proliferation compared with glucocerebroside or ceramides (Jia et al., 2016). SC-LCBs protected against high fat diet (HFD)-induced metabolic disorders in mice (Liu et al., 2015). SC-LCBs also induced apoptosis in human hepatoma HepG2 cells through decreasing phosphorylated Akt and increasing death receptor-5 (Hossain, Sugawara, & Hirata, 2013). Our current studies proved that SC-LCBs inhibited adipogenesis and regulated lipid metabolism in 3T3-L1 adipocytes (Tian et al., 2016), and reduced hepatic endoplasmic reticulum stress and inflammation in obesity mice (Hu, Wang, Wang, Xue, & Wang, 2017). However, the renoprotective effects of LCBs in type 2 diabetes mellitus have not been verified. This study was conducted to evaluate the renoprotective action of LCBs in type 2 diabetic mice. Furthermore, LCBs-involved in the inhibition of renal fibrosis and apoptosis was also investigated.
Section snippets
Isolation of LCBs
The sea cucumber, Cucumaria frondosa, was gained at the Nanshan seafood market in Qingdao, China. LCBs from Cucumaria frondosa (Cf-LCBs) were extracted and analyzed as the previous study (Hu et al., 2017). Briefly, total lipids were extracted using chloroform-methanol (2:1 v/v). The lipids were hydrolyzed with 4 M KOH in methanol 2 h at 37 °C, and subsequently with chloroform-methanol-water (2:1:0.9 v/v/v). The chloroform layer was concentrated in vacuum, and then under HCl acidolysis 16 h at
LCBs lost body weight and improved insulin resistance
The STZ/HFD treated mice had significantly higher fasting blood glucose and serum insulin concentrations (p < .01 vs. control, Table 1). The OGTT and IITT also showed severely impaired glucose tolerance and insulin tolerance in STZ/HFD animals (Fig. 1B–E), showing that STZ/HFD treatment caused insulin dysfunction and hyperglycemia. Obesity, as indicated by body weight, was also significantly greater in STZ/HFD mice (Fig. 1A and Table 1). These changes showed that the STZ/HFD-treated mice
Discussion
Elevated blood glucose and circulatory inflammation evoke renal damage and dysfunction (Pan et al., 2014, Rhee et al., 2017). Previous studies exhibited that LCBs reduced blood glucose and inhibit inflammatory response. Here, this study demonstrated that LCBs protected kidneys against damage and dysfunction in STZ/HFD-induced type 2 diabetic mice, and this effect was associated with significant reductions in blood glucose, insulin resistance, obesity, UACR, GBM thickening, renal inflammation,
Conclusions
In conclusion, we have demonstrated that LCBs inhibited renal damage and dysfunction in type 2 diabetic mice, which were associated with the improvement in insulin resistance, hyperglycemia, hyperlipidemia, obesity, and renal inflammation. Inhibition of TGF-β/Smad signal transduction was involved in LCBs-ameliorated renal fibrosis. LCBs suppressed renal apoptosis through activation of PI3K/Akt and ERK pathways. All the results suggest that LCBs may be novel and significant functional foods for
Acknowledgements
The research was supported by Zhejiang Provincial Natural Science Foundation of China (LQ16C200004) and Science and Technology project of Zhoushan (2015C21014 & 2016C41012).
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