The efficacy of gliquidone for the treatment of diabetic nephropathy was investigated by implanting micro-osmotic pumps containing gliquidone into the abdominal cavities of Goto-Kakizaki (GK) rats with diabetic nephropathy. Blood glucose, 24 h urinary protein, and 24 h urinary albumin levels were measured weekly. After 4 weeks of gliquidone therapy, pathological changes in the glomerular basement membrane (GBM) were examined using an electron microscope. Real-time PCR, western blotting, and immunohistochemistry were employed to detect glomerular expression of receptors for advanced glycation end products (RAGE) (AGER), protein kinase C β (PKCβ), and protein kinase A (PKA) as well as tubular expression of the albumin reabsorption-associated proteins: megalin and cubilin. Human proximal tubular epithelial cells (HK-2 cells) were used to analyze the effects of gliquidone and advanced glycation end products (AGEs) on the expression of megalin and cubilin and on the absorption of albumin. Gliquidone lowered blood glucose, 24 h urinary protein, and 24 h urinary albumin levels in GK rats with diabetic nephropathy. The level of plasma C-peptide increased markedly and GBM and podocyte lesions improved dramatically after gliquidone treatment. Glomerular expression of RAGE and PKCβ decreased after gliquidone treatment, while PKA expression increased. AGEs markedly suppressed the expression of megalin and cubulin and the absorption of albumin in HK-2 cells in vitro, whereas the expression of megalin and cubilin and the absorption of albumin were all increased in these cells after gliquidone treatment. In conclusion, gliquidone treatment effectively reduced urinary protein in GK rats with diabetic nephropathy by improving glomerular lesions and promoting tubular reabsorption.
Jian-Ting Ke, Mi Li, Shi-Qing Xu, Wen-Jian Zhang, Yong-Wei Jiang, Lan-yun Cheng, Li Chen, Jin-Ning Lou and Wei Wu
Can Liu, Mian Zhang, Meng-yue Hu, Hai-fang Guo, Jia Li, Yun-li Yu, Shi Jin, Xin-ting Wang, Li Liu and Xiao-dong Liu
Panax ginseng is one of the most popular herbal remedies. Ginsenosides, major bioactive constituents in P. ginseng, have shown good antidiabetic action, but the precise mechanism was not fully understood. Glucagon-like peptide-1 (GLP1) is considered to be an important incretin that can regulate glucose homeostasis in the gastrointestinal tract after meals. The aim of this study was to investigate whether ginseng total saponins (GTS) exerts its antidiabetic effects via modulating GLP1 release. Ginsenoside Rb1 (Rb1), the most abundant constituent in GTS, was selected to further explore the underlying mechanisms in cultured NCI-H716 cells. Diabetic rats were developed by a combination of high-fat diet and low-dose streptozotocin injection. The diabetic rats orally received GTS (150 or 300 mg/kg) daily for 4 weeks. It was found that GTS treatment significantly ameliorated hyperglycemia and dyslipidemia, accompanied by a significant increase in glucose-induced GLP1 secretion and upregulation of proglucagon gene expression. Data from NCI-H716 cells showed that both GTS and Rb1 promoted GLP1 secretion. It was observed that Rb1 increased the ratio of intracellular ATP to ADP concentration and intracellular Ca2 + concentration. The metabolic inhibitor azide (3 mM), the KATP channel opener diazoxide (340 μM), and the Ca2 + channel blocker nifedipine (20 μM) significantly reversed Rb1-mediated GLP1 secretion. All these results drew a conclusion that ginsenosides stimulated GLP1 secretion both in vivo and in vitro. The antidiabetic effects of ginsenosides may be a result of enhanced GLP1 secretion.
Lili Men, Junjie Yao, Shanshan Yu, Yu Li, Siyuan Cui, Shi Jin, Guixin Zhang, Decheng Ren and Jianling Du
The induction of endoplasmic reticulum (ER) stress is associated with adipogenesis, during which the inositol-requiring enzyme 1 alpha (IRE1α)-X-box-binding protein 1 (XBP1) pathway is involved. Selenoprotein S (SelS), which is an ER resident selenoprotein, is involved in ER homeostasis regulation; however, little is known about the role of SelS in regulating adipogenesis. In vivo studies showed that SelS protein levels in white adipose tissue were increased in obese subjects and high-fat diet (HFD)-fed mice. Moreover, we identified that SelS protein levels increased in the early phase of adipogenesis and then decreased in the late phase during adipogenesis. Overexpression of SelS promoted adipogenesis. Conversely, knockdown (KD) of SelS resulted in the inhibition of adipogenesis, which was related to increasing cell death, decreased mitotic clonal expansion, and cell cycle G1 arrest. In vivo studies also showed that ER stress markers (p-IRE1α/IRE1α, XBP1s, and Grp78) were significantly increased with upregulating of SelS expression in subcutaneous and visceral adipose tissues in the obese subjects and HFD-fed mice. Furthermore, in SelS KD cells, the levels of Grp78 were increased and the levels of p-IRE1α/IRE1α were unchanged , but mRNA levels of spliced XBP1 (XBP1s) produced by IRE1α-mediated splicing were decreased, suggesting a role of SelS in the modulation of IRE1α-XBP1 pathway. Moreover, inhibition of adipogenesis by SelS suppression can be rescued by overexpression of XBP1s. Thus, SelS appears to function as a novel regulator of adipogenesis through the IRE1α-XBP1 signaling pathway.