β-N-Oxalyl-L-α,β-diaminopropionic acid from Panax notoginseng plays a major role in the treatment of type 2 diabetic nephropathy.

Diabetic nephropathy (DN) is one of the most serious and dangerous chronic complications of diabetes mellitus.Panax notoginseng has been widely used with great efficacy in the long-term treatment of kidney disease. However, the mechanism by which it exerts its effects has not been fully elucidated. We sought to identify the major components ofPanax notoginseng that are effective in reducing the symptoms of DN in vitro and in vivo. Inhibition of cell proliferation and collagen secretion were used to screen the ten most highly concentrated components ofPanax notoginseng. The STZ-induced DN rat model on a high-fat-high-glucose diet was used to investigate the renal protective effect of Panax notoginseng and dencichine and their underlying molecular mechanisms. Among the ten components analysed, dencichine (β-N-oxalyl-L-α,β-diaminopropionic acid) was the most protective against DN. Dencichine andPanax notoginseng attenuated glucose and lipid metabolic disorders in STZ-induced DN rats on a high-fat-high-glucose diet. In the untreated DN rats, we observed albuminuria, renal failure, and pathological changes. However, treatment with dencichine and Panax notoginseng alleviated these symptoms. We also observed that dencichine suppressed the expression of TGF-β1 and Smad2/3, which mediates mesangial cell proliferation and extracellular matrix (ECM) accumulation in the glomerulus, and enhanced the expression of Smad7, the endogenous inhibitor of the TGF-β1/Smad signalling pathway. From these results, we concluded that dencichine is the main compound inPanax notoginseng that is responsible for alleviating renal injury in the experimental DN model. Its mechanism may be related to the reduction of the deposition of ECM in glomeruli and inhibition of the epithelial mesenchymal transformation (EMT) by inhibition of the TGF-β1/Smad signalling pathway.

Li J ，Qiu P ，Wang S ，Wu J ，He Q ，Li K ，Xu L ... -  《-》

Dencichine ameliorates kidney injury in induced type II diabetic nephropathy via the TGF-β/Smad signalling pathway.

Diabetic nephropathy (DN), a common complication associated with both type I and type II diabetes mellitus (DM), is a major cause of chronic nephropathy and a common cause of end-stage renal diseases (ESRD) throughout the world. This study is aimed to determine whether dencichine (De) can ameliorate renal damage in high-glucose-and-fat diet combined STZ (streptozocin) induced DN in type II DM rats and to investigate the potential underlying mechanisms. Markers of metabolism, diabetes, and renal function, and levels of extracellular matrix (ECM) collagen I (Col I), collagen IV (Col IV), fibronectin (FN) and laminin (LN), and of proteins in the TGF-β/Smad pathway were analysed through RT-PCR, western blot, immunofluorescence and immunohistochemistry. The results show that De significantly alleviates metabolism disorder, improved renal function, relieved pathological alterations in the glomerulus of DN rats, decreased ECM deposition and increased the ratio of matrix metalloproteinase (MMP)-9 to tissue inhibitor of metalloproteinase (TIMP)-1 both in vivo and in vitro. Moreover, De negatively regulated TGF-β/Smad signalling pathway and increased the expression of Smad7, an endogenic inhibitory Smad located downstream of the signalling pathway. In conclusion, we provide experimental evidence indicating that the renoprotective effect of De could significantly prevent the progression of DN possibly attribute to down-regulation of the TGF-β/Smad pathway and rebalance the deposition and degradation of ECM proteins.

Jie L ，Pengcheng Q ，Qiaoyan H ，Linlin B ，Meng Z ，Fang W ，Min J ，Li Y ，Ya Z ，Qian Y ，Siwang W ... -  《-》

Sitagliptin ameliorates diabetic nephropathy by blocking TGF-β1/Smad signaling pathway.

Wang D ，Zhang G ，Chen X ，Wei T ，Liu C ，Chen C ，Gong Y ，Wei Q ... -  《-》

A bioinformatics and network pharmacology approach to the mechanisms of action of Shenxiao decoction for the treatment of diabetic nephropathy.

The epithelial-to-mesenchymal transition (EMT) of renal tubular epithelial cells is the main pathological alteration in diabetic nephropathy (DN). Traditional Chinese medicine (TCM) has been used for the treatment of DN in clinical practice and has been proven to be effective. This aim of this study was to shed light on the efficacy of Shenxiao decoction (SXD) on the EMT of renal tubular epithelial cells and the molecular mechanisms of SXD in mice with DN, as well as on the high glucose (HG)- and TGF-β1-induced EMT of NRK-52E and HK-2 cells. A bioinformatics and network pharmacology method were utilized to construct the active ingredient-target networks of SXD that were responsible for the beneficial effects against DN. The effects of RUNX3 were validated in HG- and TGF-β1-induced EMT processes in NRK-52E and HK-2 cells. Bioinformatics analysis revealed that 122 matching targets were closely associated with the regulation of cell migration and the AGE-RAGE signaling pathway in diabetic complications. The results also revealed that, relative to the mice with DN, the mice in the treatment group had an improved general state and reduced blood glucose levels. The degradation of renal function was ameliorated by SXD. Moreover, the protective effects of SXD were also observed on renal structural changes. Furthermore, SXD suppressed the activation of the transforming growth factor (TGF)-β1/Smad pathway and upregulated the RUNX3 and E-cadherin levels and downregulated the extracellular matrix (ECM) protein levels in mice with DN. SXD was further found to prevent the HG- and TGF-β1-induced EMT processes in NRK-52E and HK-2 cells. Additionally, the overexpression of RUNX3 markedly inhibited the EMT and TGF-β1/Smad pathway induced by HG and TGF-β1 in NRK-52E and HK-2 cells. Taken together, these results suggest that SXD maybe alleviate EMT in DN via the inhibition of the TGF-β1/Smad/RUNX3 signaling pathway under hyperglycemic conditions.

Mou X ，Zhou DY ，Zhou D ，Liu K ，Chen LJ ，Liu WH ... -  《-》

[Effects of centella asiatica granule on the expression of TGF-β(1) and related down-stream signals in rats with early diabetic nephropathy].

Ma JW ，Wang HT ，Liu HF ，Ding Y ，Bai JQ ，Zhang Z ... -  《-》