Huangqi–Danshen decoction (HDD) is a commonly used drug pair for clinical treatment of chronic kidney disease (CKD) in traditional Chinese medicine with good efficacy. However, the potential mechanisms of this action have not been well elucidated. The aim of this study was to explore the metabolic profiling variations in response to HDD treatment in a CKD rat model. CKD rat model was induced by adding 0.75% adenine to the diet for 4 weeks. The rats in the treatment group received HDD extract orally at the dose of 4.7 g/kg/day during the experiment. At the end of the experiment, serum and kidney samples were collected for biochemical and pathological examination. Ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-QTOF/MS) was used to analyze metabolic profiling variations in the kidney. The results showed that treatment with HDD markedly attenuated kidney injury and improved renal function. A total of 28 metabolites contributing to CKD phenotype were found and identified in the kidney samples. The primary metabolic pathways disordered in the kidney of CKD rats were glycerophospholipid metabolism, glycosylphosphatidylinositol-anchor biosynthesis, and citrate cycle. Partial least squares discriminant analysis (PLS-DA) score plot showed that the three groups of renal samples were obviously divided into three categories, and the metabolic trajectory of the HDD treatment group moved to the control group. (E)-Piperolein A, phosphatidylcholines (PC) (18:1/22:6), phosphatidylinositols (PI) (13:0/18:1), PI (15:0/20:3), phosphatidylserines (PS) (O-20:0/12:0), and triglyceride (TG) (22:4/24:0/O-18:0) represented potential biomarkers of the renoprotective effects of HDD against CKD. In conclusion, HDD has renoprotective effect against adenine-induced CKD, which may be mediated via partially restoration of perturbed metabolism in the kidney.

Introduction: Jian-Pi-Yi-Shen pill (JPYSP) is a Chinese medicine formula developed for the treatment of anaemic patients with chronic kidney disease (CKD). Objective: To investigate the chemical profile of JPYSP in the treatment of renal anaemia. Methods: A method coupling ultra-performance liquid chromatography with quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF-MS/MS) was established to characterise the chemical constituents present in JPYSP. Subsequently, a high-performance liquid chromatography method coupled with triple-quadrupole tandem mass spectrometry (HPLC-QQQ-MS/MS) was developed to quantify the major constituents from the identified compounds related to the treatment of CKD and anaemia. Results: A total of 71 compounds were tentatively identified from JPYSP, including saponins, flavonoids, sesquiterpenoids, coumarins, phenylpropanoids, anthranones, anthraquinones, tannins, phenolic acids and others. Amongst them, 12 compounds (i.e. astragaloside IV, calycosin, calycosin 7-O-glucoside, salvianolic acid A, rosmarinic acid, rhein, liquiritin, formononetin, atractylenolide I, dioscin, tanshinone IIA, and acteoside) were further quantified simultaneously by HPLC-QQQ-MS/MS. Conclusion: The newly developed approach is suitable for the chemical profiling analysis and quality control of JPYSP, and could lead to additional pharmacodynamic studies involving the components of JPYSP.

Jian-Pi-Yi-Shen (JPYS) is one of the herbal medicines for treatment of anemic patients with chronic kidney disease (CKD). However, less of scientific evidence to support JPYS involved in treating anemia has been revealed. Here, an animal study was performed to investigate its hematopoietic activities and the underlying mechanism. The 5/6 nephrectomized inductions of CKD anemic rats were randomly divided into two groups: CKD group and JPYS group. Sham-operated rats served as sham group. JPYS (1.36 g/kg/d) was administered orally to CKD rats daily for six consecutive weeks. Results showed that JPYS treatment notably improved renal function and pathological injury in CKD rats. JPYS also restored the hematological parameters, including red blood cells, hemoglobin, and hematocrit. In parallel, the reduction level of EPO was reversed by JPYS. Furthermore, JPYS induced the accumulation of hypoxia inducible factor (HIF)-α protein expression. Collectively, these results provide convincing evidence for JPYS decoction in ameliorating CKD-associated anemia, and its mechanism might be related to regulate EPO production via HIF signaling pathway.

Chronic kidney disease (CKD) is a leading public health problem with high morbidity and mortality. However, the therapies remain limited. Traditional Chinese medicine (TCM) has been used for treating kidney disease for thousands of years and is an effective alternative treatment for CKD patients in China and other Asian countries. In the present study, we aimed to investigate the effect and mechanism of Huangqi-Danshen decoction (HDD), a TCM herbal decoction, on treating CKD. CKD rat model was induced by adding 0.75% adenine to the diet for 4 weeks. HDD extract was administrated orally to CKD rats at the dose of 4.7 g/kg/d for consecutive 4 weeks in adenine-induced CKD rats. Kidney function was evaluated by the levels of serum creatinine (Scr) and blood urea nitrogen (BUN). The pathological changes of kidney tissues were observed by periodic acid-Schiff (PAS) and Masson's trichrome staining. The proteins expression of renal fibrosis and mitochondrial dynamics were determined and quantified by Western blot analysis. CKD rats showed obvious decline in renal function as evidenced by increased levels of Scr and BUN, which were blunted by HDD treatment. HDD could also improve tubular atrophy and interstitial fibrosis of CKD rats. Moreover, HDD downregulated fibronectin, type IV collagen, and α-smooth muscle actin expression in CKD rats. Furthermore, mitochondrial dynamics was disturbed in CKD rats, which manifested as increased mitochondrial fission and decreased mitochondrial fusion. HDD treatment restored mitochondrial dynamics in CKD rats by repressing dynamin-related protein 1 and Mid 49/51 expression, promoting mitofusin 2 expression, and suppressing optic atrophy 1 proteolysis. In conclusion, HDD could significantly retard CKD progression through modulating mitochondrial dynamics.

Gut dysbiosis contributes to the development and progression of chronic kidney disease (CKD) and its complications. However, the effect of drugs on the gut microbiota of CKD patients and its influence on treatment outcomes remains to be explored. Here, we assessed whether the response of gut microbiota to the traditional Chinese medicine Jian-Pi-Yi-Shen (JPYS) decoction differed from that to piperazine ferulate (PF), a kidneytargeted drug, by 16S rDNA sequencing, and whether the difference could be linked with drug-specific clinical outcomes. We showed that both JPYS and PF improved renal function, but only JPYS was able to restore the blood reticulocyte counting and serum calcium level in CKD rats. We also found that weighted UniFrac beta-diversity of the gut microbiome of the JPYS treated rats was significantly different from that of PF. Microbiome markers of drug-specific response were identified and subjected to correlation network analysis, together with clinical parameters and KEGG pathways. Among the microbiome markers of CKD, Corynebacterium was found to form a network hub that was closely correlated with the JPYS responder Enterococcus, suggesting a potential indirect impact of JPYS on Corynebacterium via interspecies interactions. We also identified two network hubs of the PF responder Blautia and the JPYS-only marker Coprococcus, which were connected with many genera and clinical parameters. They might serve as keystone taxa driving the response of gut microbiota to the drugs and influence host outcomes. Moreover, the JPYS-only marker Clostridium_XIVb was found to be connected to many pathways that are associated with CKD progression and might account for the improved outcomes in the JPYS treated rats. At last, the identified keystone markers of drug