Septic acute kidney injury (AKI) is a frequent and serious complication of sepsis in critically ill patients associated with high morbidity and mortality. However, the treatment of septic AKI has still been beyond satisfaction. Dihydroartemisinin (DHA) is a semisynthetic derivative of artemisinin and is proposed as a potential agent for treating cancer and inflammatory diseases. In the present study, we aimed to investigate the effect of DHA on lipopolysaccharide (LPS)-induced AKI and the underlying mechanism. Male C57BL/6 mice were pretreated with or without DHA (20 mg/kg/d) for two days, and then were treated with one dose LPS (10 mg/kg) intraperitoneal injection to induce septic AKI. Twenty-four hours after LPS injection, blood samples and kidneys were collected for evaluation. The results indicated that DHA significantly ameliorated LPS-induced AKI as evidenced by improvement of renal function (serum creatinine and blood urea nitrogen), amelioration of renal pathological injury, and inhibition of tubular cell apoptosis. Meanwhile, DHA also strikingly attenuated inflammatory response, suppressed NF-κB signaling pathway activation, and inhibited oxidative stress in LPS-challenged mice. In conclusion, DHA could protect against LPS-induced AKI possibly by anti-inflammatory and antioxidant activities.

Macrophage polarization has been reported to induce podocyte injury, which is a typical characteristic of diabetic nephropathy (DN). Trichosanthes kirilowii is an herb showing renal protective effect as well as immune-regulating effect. Therefore, it was hypothesized that the renal protective effect of Trichosanthes kirilowii was associated with its modulation on macrophage polarization. In the current study, we tested the hypothesis by subjecting DN rats to treatment of Trichosanthes kirilowii lectin (TKL), an active component of Trichosanthes kirilowii. DN was induced using streptozocin (STZ) method, and after 3 days, treatments were performed with different doses of TKL for eight weeks. The effect of TKL on the renal function, structure, and inflammation was assessed. To explain the pathway mediating the effect of TKL on renal tissues, the expressions of markers involved in macrophage polarization, podocyte proliferation, and Notch signaling were determined. Moreover, the DN rats were further administrated with Notch signaling inhibitor, Dibenzazepine (DIB), to verify the key role of Notch signaling in the renal protective effect of TKL. STZ induced damages in renal function and structure, which was attenuated by TKL of different doses. Moreover, STZ also increased the production of TNF-α and iNOS while suppressed the production of IL-10 and arginase-1 (Arg-1). The induced inflammation by STZ was inhibited by TKL. The polarization of macrophage into M1 type during the development of DN was blocked by TKL, contributing to the increased proliferation potential of podocytes. Regarding Notch signaling, TKL administration inhibited the activation of the pathway by suppressing the expression of Notch1, NICD1, and Hes1. The administration of DIB had similar effect to that of TKL administration on renal function and structure. The study for the first time showed that TKL attenuated deterioration in renal structure and function by increasing M2 macrophage proportion via inhibition of Notch signaling.

Background: Chronic kidney disease (CKD) is usually insidious, and most affected individuals are asymptomatic until the disease becomes advanced. The effective treatment of CKD would rely on the incorporation of multidisciplinary approaches. Astragalus membranaceus (AM) and Curcuma zedoaria (CZ) have been widely used in the treatment of CKD. However, the mechanism of AM and CZ in the treatment of CKD is still unclear.Methods: This study was designed to evaluate the effects of AM and CZ on adenine-induced rats and to investigate the underlying mechanism by using metabolomic analysis. Addition of 0.75% adenine to the diet of rats for 3 weeks induced the animal model of CKD. The rats in the treatment group were treated with AM and CZ (2.1 g/kg/day) for 4 weeks. Blood and kidney samples were collected for biochemical and histological examination. Ultra-high-performance liquid chromatography/Q Exactive HFX mass spectrometer (UHPLC-QE-MS) was applied to analyze metabolic profiling variations in the kidney.Results: The results showed that AM and CZ could significantly reduce serum creatinine (Scr) and blood urea nitrogen (BUN) levels in CKD rats and alleviate renal pathological injury. By comparing the endogenous components of the normal group and the model group in positive ion mode and negative ion mode, a total of 365 and 155 different metabolites were screened, respectively. A total of 117 and 73 metabolites with significantly different expressions were identified between model group and AM and CZ group in positive ion mode and negative ion mode, respectively. The pivotal pathways affected by AM and CZ included nicotinate and nicotinamide metabolism, and glycine, serine and threonine metabolism. Furthermore, significant changes in metabolites in CKD rats after AM and CZ therapies were observed, including L-Threonine, D-pantothenic acid, and nicotinamide. Moreover, we found that AM and CZ significantly reduced renal fibrosis and inflammation in CKD rats, which may be related to the regulation of SIRT1/JNK signaling pathway.Conclusion: In conclusion, AM and CZ significantly reduced renal fibrosis and inflammation in CKD rats, which may be related to the regulation of SIRT1/JNK signaling pathway. Furthermore, L-Threonine, D-pantothenic acid, and nicotinamide may be potential biomarkers for the progression and treatment of CKD.

Trichosanthes kirilowii lectin (TKL) has been reported to exert hypoglycemic effects in alloxan-induced diabetic mice. However, there is no evidence showing that it helps to prevent diabetic nephropathy (DN). We used a high glucose (HG)-induced HK-2 cell model and a streptozocin (STZ)-induced Wistar rat model to investigate the effects of TKL on DN, as well as the mechanisms for those effects. Our results showed that TKL significantly increased the viability of HG-treated HK-2 cells and inhibited cell apoptosis. In vivo experiments demonstrated that TKL attenuated STZ-induced histopathological damage and the inflammatory response in rat kidney tissues. Pre-treatment of HK-2 cells or STZ-treated rats with polyinosinic acid (Poly IC), an inhibitor of lectin-like oxLDL receptor 1 (LOX1), blocked the protective effect of TKL against HG- or STZ-induced damage to kidney tissue, indicating that TKL might exert its effect via LOX1-mediated endocytosis. Additional results suggested that TKL inhibits the phosphorylation of IκB kinase β (IKKβ) and the nuclear factor-κB (NF-κB) inhibitor protein (IκBα), and thereby reduces the nuclear translocation of NF-κB (p65). ChIP assay data indicated that TKL markedly inhibits the binding of p65 to the CASP9 gene in HG-treated HK-2 cells, subsequently suppressing transcription of the CASP9 gene. In the dual-luciferase reporter assay, TKL significantly inhibited luciferase activity in cells co-transfected with p65 and a wild-type capase-9 construct instead of mutated caspase-9 constructs. Taken together, our results show that TKL helps to protect against DN by inhibiting the LOX1/NF-κB/caspase-9 signaling pathway, suggesting TKL as a promising agent for treating DN.

Background: Diabetic kidney disease (DKD) is the most common cause of end-stage renal disease. The effective treatment of DKD would rely on the incorporation of a multi-disciplinary. Studies have shown that Tripterygium wilfordii Hook.F. and Trichosanthes kirilowii Maxim have remarkable curative effects in treating DKD, but their combination mechanism has not been fully elucidated.Methods: We explored the mechanism of Tripterygium wilfordii Hook.F.-Trichosanthes kirilowii Maxim decoction (Leigongteng-Tianhuafen Decoction,LTD) in the treatment of DKD by network pharmacology and molecular docking. The main active components and action targets of LTD were collected from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) database. The speculative targets of DKD were obtained from GeneCards, DisGeNET, and Online Mendelian Inheritance in Man (OMIM) databases. Then, an herb-component-target network was constructed based on the above analyses. The biological function of targets was subsequently investigated, and a protein-protein interaction (PPI) network was constructed to identify hub targets of DKD. The gene ontology (GO) function enrichment analysis and kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis were performed by RStudio. Finally, molecular docking was performed by AutoDock Vina and PyMOL software to explore the interaction between compounds and targets. Furthermore, the DKD model of human renal tubular cells (HK-2) induced by high glucose (HG) was selected, and the predicted results were verified by western blot analysis and immunofluorescence.Results: A total of 31 active components of LTD were screened out, and 196 targets were identified based on the TCMSP database. A total of 3,481 DKD related targets were obtained based on GeneCards, DisGeNET, and OMIM databases. GO function enrichment analysis included 2,143, 50, and 167 GO terms for biological processes (BPs), cellular composition (CCs), and molecular functions (MFs), respectively. The top 10 enrichment items of BP annotations included response to lipopolysaccharide, response to molecule of bacterial origin, response to extracellular stimulus, etc. CC was mainly enriched in membrane raft, membrane microdomain, plasma membrane raft, etc. The MF of LTD analysis on DKD was predominately involved in nuclear receptor activity, ligand-activated transcription factor activity, RNA polymerase II-specific DNA-binding transcription factor binding, etc. The involvement signaling pathway of LTD in the treatment of DKD included AGE-RAGE signaling pathway in diabetic complications, IL-17 signaling pathway, insulin resistance, TNF signaling pathway, etc. Molecular docking results showed that kaempferol, triptolide, nobiletin, and schottenol had a strong binding ability to PTGS2 and RELA. Furthermore, the in vitro experiments confirmed that LTD effectively decreased the expression of PTGS2, NF-κB, JNK, and AKT in the HG-induced DKD model.Conclusion: The findings of this study revealed that the therapeutic efficacy of LTD on DKD might be achieved by decreasing the expression of PTGS2, NF-κB, JNK, and AKT, which might improve insulin resistance, inflammation, and oxidative stress. These findings can provide ideas and supply potential therapeutic targets for DKD.

Diabetic kidney disease (DKD) is an increasing global public health problem. Triptolide (TP) has a good therapeutic effect on DKD and is widely used in China. However, the mechanism of TP is still unclear. Db/db mice models were subjected to TP for 12 weeks. UHPLC-QE-MS and 16S rRNA amplicon sequencing were used to investigate the correlations between the metabolome, microbiome, and DKD-related indicators under DKD condition. TP demonstrated significant nephroprotective effects in db/db mice, ameliorated renal functional impairment and structural damage while attenuated inflammatory responses associated with DKD. Notably, TP administration effectively restored gut microbiota dysbiosis in db/db mice. Comparative analysis identified ten altered microbial taxa across groups, including Bifidobacterium, Erysipelotrichaceae_U-CG003, Herminiimonas, Domibacillus, Methylobacterium-Methylorubrum, Phascolarctobacterium, Dorea, Ralstonia, UCG-002, and Dubosiella, suggesting their potential utility as discriminative biomarkers for DKD progression and therapeutic response. Metabolomic profiling revealed 11 significantly perturbed metabolites, with small molecule pathway database (SMPDB) enrichment analysis highlighting three critical metabolic pathways: vitamin K metabolism, propionate metabolism, and steroid biosynthesis. Mechanistic investigations suggest that TP may reduce the inflammatory response through the JNK/STAT/P53 pathway, regulate the changes of intestinal flora, and correct renal metabolic disorders to exert renal protection. TP may play a renal protective role by regulating the changes of intestinal microflora and correcting renal metabolic disorders, which may be related to the JNK/STAT/P53 pathway involved in reducing the inflammatory response. In addition, Vitamin K2 has a synergistic anti-inflammatory effect with TP.