Jiedu Tongluo Baoshen formula enhances podocyte autophagy and reduces proteinuria in diabetic kidney disease by inhibiting PI3K/Akt/mTOR signaling pathway.

Traditional Chinese medicine (TCM) has been applied to diabetic kidney disease (DKD). A large number of animal trials each year focus on TCM for DKD, but the evidence for these preclinical studies is not clear. The aim of this study was to study the therapeutic effect of Jiedu Tongluo Baoshen formula (JTBF) on DKD proteinuria and renal protection. At the same time, it is verified that JTBF can reduce podocyte injury by enhancing autophagy function, and then achieve the effect of proteinuria. We use high performance liquid chromatography to detect and analyze the fingerprint of JTBF to find the chemical composition. Subsequently, we constructed a DKD rat model induced by high-fat diet and streptozocin (HFD + STZ). Urine and blood biochemical automatic analyzer were used to detect 24-h urine protein quantification (24 h-UP) and renal function. The renal pathological changes were observed by H&E and transmission electron microscopy (TEM), and the levels of autophagy-related proteins and mRNA in podocytes were detected by immunohistochemistry, RT-qPCR and Western Blot. The chemical composition of JTBF was screened from traditional Chinese medicine systems pharmacol (TCMSP) and PubChem databases, and the potential targets and associated pathways of JTBF were predicted using kyoto encyclopedia of genes and genomes (KEGG) and protein-protein interaction (PPI) network analysis in network pharmacology, and confirmed in animal experiments and histopathological methods. We discovered 77 active ingredients of JTBF. Through animal experiments, it was found that JTBF reduced 24 h-UP and promoted the expression of podocin, nephrin, and WT-1 in podocytes, thereby reducing podocyte damage. At the same time, JTBF activates the expression of podocyte autophagy-related proteins (beclin-1, LC3 and P62). Subsequently, through network pharmacology predictions, 208 compounds were obtained from JTBF, and phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) was a potential signal pathway. JTBF was obtained in DKD rat kidney tissue to inhibit the expression of PI3K, Akt and mTOR related proteins. JTBF enhance podocyte autophagy to reduce podocyte damage, thereby effectively treating DKD proteinuria and protecting kidney function.

Jin D ，Liu F ，Yu M ，Zhao Y ，Yan G ，Xue J ，Sun Y ，Zhao D ，Li X ，Qi W ，Wang X ... -  《-》

Jiedu Tongluo Baoshen formula enhances renal tubular epithelial cell autophagy to prevent renal fibrosis by activating SIRT1/LKB1/AMPK pathway.

Renal fibrosis, an important pathological change in the development of diabetic kidney disease (DKD), urgently needs new treatment methods clinically. The Jiedu Tongluo Baoshen (JTBF) formula was created based on the theory of toxic damage to the kidney collaterals, and a variety of active ingredients in JTBF have inhibitory effects on epithelial-mesenchymal transition (EMT) and extracellular matrix (ECM). In this study, the Ultra Performance Liquid Chromatography (UPLC) was employed to analyze the effective ingredients in the JTBF formula. After screening in the PubChem database, we identified 94 active compounds of JTBF and predicted the SIRT1 pathway as potential targets through network pharmacology. In addition, in the high fat diet (HFD)+Streptozocin (STZ)-induced DKD rat model and high glucose (HG)-induced NRK-52E cell model, JTBF treatment activates the phosphorylation of LKB1 and AMPK and enhances the autophagy activity of NRK-52E cells, thereby reducing the accumulation of EMT and ECM. These results have been confirmed in vivo and in vitro experiments. JTBF enhances the autophagy activity of renal tubular epithelial cells and inhibits the progression of DKD renal fibrosis by activating the SIRT1/LKB1/AMPK signal pathway. This study provides new insights into the molecular mechanism of JTBF to prevent and treat DKD renal fibrosis.

Jin D ，Zhao Y ，Sun Y ，Xue J ，Li X ，Wang X ... -  《-》

Qizhi Jiangtang capsule activates podocyte autophagy in diabetic kidney disease by inhibiting phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin pathways.

Zhaoan G ，Lina S ，Yingying L ，Ruifeng LI ，Chong L ，Ke D ，Jing S ，Jun S ... -  《-》

Paecilomyces cicadae-fermented Radix astragali activates podocyte autophagy by attenuating PI3K/AKT/mTOR pathways to protect against diabetic nephropathy in mice.

Radix astragali, a medicinal material for tonifying Chinese Qi, has widely been used for the treatment of Kidney disease in China and East Asia, especially in reducing the apoptosis of glomerular podocytes. Paecilomyces Cicadidae is a medicinal and edible fungus. In recent years, the application of traditional Chinese medicine (TCM) in solid-state fermentation of edible and medicinal fungi has become a hot issue. Fermentation is a special method to change the properties of TCM. Therefore, the potential roles and molecular mechanisms on podocytes of solid-state fermentation products of Radix astragali and Paecilomyces cicadidae (RPF) in diabetic nephropathy (DN) were studied. In vivo, the effect of RPF and Radix astragali on DN in mice was evaluated by detecting the biochemical indexes of blood and urine, renal function and podocyte integrity. In vitro, the expression of podocyte marker protein, autophagy marker protein and PI3K/AKT/mTOR signaling pathway protein were detected by Western blotting using a high glucose-induced podocyte injury model. The results showed that RPF had a significant alleviative effect on DN mice. RPF can significantly reduce urine protein, serum creatinine, and blood nitrogen urea in DN mice. Morphological analysis showed that RPF could improve kidney structure of DN and reduce the apoptosis of podocytes, and the effect was better than Radix astragali. In vitro results indicated that RPF could enhance autophagy and protect podocytes by inhibiting the PI3K/AKT/mTOR signaling pathway. In summary, RPF has better effect on delaying the development of DN than Radix astragali. RPF enhances autophagy in podocytes and delays DN probably by inhibiting the PI3K/AKT/mTOR signaling pathway.

Yang F ，Qu Q ，Zhao C ，Liu X ，Yang P ，Li Z ，Han L ，Shi X ... -  《-》

Tongluo Digui decoction treats renal injury in diabetic rats by promoting autophagy of podocytes.

Han J ，Zhang Y ，Shi X ，Peng Z ，Xing Y ，Pang X ... -  《-》