Long-chain bases from sea cucumber inhibits renal fibrosis and apoptosis in type 2 diabetic mice

doi:10.1016/j.jff.2017.12.013

Journal of Functional Foods

Volume 40, January 2018, Pages 760-768

https://doi.org/10.1016/j.jff.2017.12.013 Get rights and content

Highlights

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LCBs significantly alleviated renal dysfunction and injure.
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Inhibition of TGF-β/Smad signal was the mechanism of LCBs attenuated renal fibrosis.
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LCBs inhibited renal apoptosis through activation of PI3K/Akt and ERK signaling.
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LCBs are novel functional factors against type 2 diabetic nephropathy.

Abstract

Long-chain bases (LCBs) from sea cucumber exert antineoplastic, antihyperglycemia and anti-inflammatory activities. However, their renoprotective effects are undiscovered. Here, we investigated the effects of LCBs on protection against type 2 diabetic nephropathy in mice. Results showed that LCBs attenuated renal dysfunction through the reductions of urine glucose and albumin-to-creatinine ratio, which are associated with the decreases in serum lipids, body weight, insulin resistance, and renal inflammation. LCBs inhibited tubular atrophy, aglomerular lipid droplet, and glomeular basement membrane thickening, and promoted brush border density, suggesting their effects on protection against renal injury. LCBs mitigated renal fibrosis through blocking transforming growth factor-β/Smad signaling. Renal apoptosis was suppressed by LCBs administration through activation of PI3K/Akt and ERK pathways. These results demonstrate that LCBs have significantly renoprotective effects via declining the progression of renal fibrosis and apoptosis. These will provide a significant implication for LCBs utilization as functional foods against type 2 diabetic nephropathy.

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).

References (43)

K.P. Alden et al.
Sphingolipid long chain base phosphates can regulate apoptotic-like programmed cell death in plants
Biochemical and Biophysical Research Communications
(2011)
S. Hu et al.
Long-chain bases from sea cucumber mitigate endoplasmic reticulum stress and inflammation in obesity mice
Journal of Food and Drug Analysis
(2017)
Y.J. Kim et al.
Pycnogenol modulates apoptosis by suppressing oxidative stress and inflammation in high glucose-treated renal tubular cells
Food and Chemical Toxicology
(2011)
H.Y. Lan et al.
TGF-β/Smad signaling in kidney disease
Seminars in Nephrology
(2012)
J. Li et al.
Rictor/mTORC2 signaling mediates TGFβ1-induced fibroblast activation and kidney fibrosis
Kidney International
(2015)
D. Pan et al.
A novel proteoglycan from Ganoderma lucidum fruiting bodies protects kidney function and ameliorates diabetic nephropathy via its antioxidant activity in C57BL/6 db/db mice
Food and Chemical Toxicology
(2014)
J.E. Shaw et al.
Global estimates of the prevalence of diabetes for 0 and 2030
Diabetes Research and Clinical Practice
(2010)
L. Sheng et al.
Epidermal growth factor receptor signaling mediates aldosterone-induced profibrotic responses in kidney
Experimental Cell Research
(2016)
D. Verzola et al.
Apoptosis in the kidneys of patients with type II diabetic nephropathy
Kidney International
(2007)
B. Wang et al.
Rutin ameliorates kidney interstitial fibrosis in rats with obstructive nephropathy
International Immunopharmacology
(2016)

P.C. Wang et al.

Anti-diabetic polysaccharides from natural sources: A review

Carbohydrate Polymers

(2016)

K.H. Yoon et al.

Epidemic obesity and type 2 diabetes in Asia

Lancet

(2006)

L.A. Allan et al.

Inhibition of caspase-9 through phosphorylation at Thr 125 by ERK MAPK

Nature Cell Biology

(2003)

G. Basañez et al.

A new view of the lethal apoptotic pore

PLoS Biology

(2012)

S. Bordbar et al.

High-value components and bioactives from sea cucumbers for functional foods – A review

Marine Drugs

(2011)

M.L. Brezniceanu et al.

Reactive oxygen species promote caspase-12 expression and tubular apoptosis in diabetic nephropathy

Journal of the American Society Nephrology

(2010)

L.C. Cantley

The phosphoinositide 3-kinase pathway

Science

(2002)

H. Chung et al.

Ghrelin inhibits apoptosis in hypothalamic neuronal cells during oxygen-glucose deprivation

Endocrinology

(2007)

I. Daehn et al.

Endothelial mitochondrial oxidative stress determines podocyte depletion in segmental glomerulosclerosis

Journal of Clinical Investigation

(2014)

Z. Fu et al.

Effects of piceatannol and pterostilbene against β-amyloid-induced apoptosis on the PI3K/Akt/Bad signaling pathway in PC12 cells

Food and Function

(2016)

M. Gangadharan Komala et al.

Linagliptin limits high glucose induced conversion of latent to active TGFß through interaction with CIM6PR and limits renal tubulointerstitial fibronectin

PLoS ONE

(2015)

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