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Jian-Pi-Yi-Shen Formula Ameliorates Oxidative Stress, Inflammation, and Apoptosis by Activating the Nrf2 Signaling in 5/6 Nephrectomized Rats.

ABSTRACT: Chronic kidney disease (CKD) is an increasing global public health problem, with high morbidity and mortality. Jian-Pi-Yi-Shen (JPYS) formula is a representative traditional Chinese medicine formula in the treatment of CKD, which is widely used in clinical practice in China. However, the underlying mechanism has not been well elucidated. In the present study, we measured the markers of apoptosis, inflammation, oxidative stress, and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling to investigate the effects of JPYS formula on renal function and fibrosis and its molecular mechanism in an established animal model of 5/6 nephrectomized (5/6Nx) rats. The results demonstrated that the JPYS formula exerted a significant preventive effect on renal dysfunction and fibrosis, based on analysis of correlative parameters such as urinary protein, SCr, BUN, glomerular sclerosis index, and tubulointerstitial fibrosis score and renal histopathology and ultrastructural pathology of CKD rats. JPYS formula also induced downregulation of gene expression associated with fibrosis, such as TGF-β and type I, III, and IV collagen. Moreover, the JPYS formula showed a significant protective effect in suppressing cell apoptosis according to the results of apoptotic indexes, including increased gene expression of Bcl-2, decreased gene expression of Bax, caspase 3, caspase 9, and the number of TUNEL-positive cells. JPYS formula also ameliorated the activation of the NF-κB-mediated inflammatory pathway, as manifested by the downregulation of gene expression of TNF-α, IL-1β, IκBα, NF-κB p65, MCP-1, CXCL1, COX-2, and iNOS in the kidney. Our evidence also suggested that the JPYS formula ameliorates oxidative stress by promoting antioxidant function according to antioxidant index indicators as an indicator of GSH, SOD, CAT, and GPx and abating excessive accumulation of the reactive oxygen species biomarkers, including ROS, TBARS, 8-oxo-dG, and MDA. The data also suggested that the JPYS formula reversed the downregulation of HO-1 and Nrf2 level and upregulation of Keap1 expression. Together, our data highlighted that the JPYS formula relieved renal oxidative injury mediated by activation of Nrf2 signaling by inhibiting inflammation and apoptosis in CKD rats.

SUBMITTER: Zhou F

PROVIDER: S-EPMC8027107 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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 kidney-targeted 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 response were validated by qPCR for their differential abundance between CKD and the two drugs. Taken together, our study revealed that the responses of gut microbiota to JPYS were distinct from that to PF, and pinpointed drug-specific keystone microbiome markers closely correlated to clinical parameters, which could serve as candidate microbiome targets for further studies on their roles in medicating the drug efficacy of TCM in CKD.

Project description:Jian-Pi-Yi-Shen (JPYS), the traditional Chinese medicine (TCM) decoction, has been commonly used to treat chronic kidney disease (CKD) and its complications such as anemia. JPYS has been previously found to induce erythropoietin (EPO) production in HEK293T cells and CKD rats. However, the mechanism of JPYS in treating anemia of CKD rats has remained largely unknown. Here, we further extend our effort to investigate the translational control of hypoxia inducible factor- (HIF-) α protein via ERK signaling and the effect on iron recycling-related protein expression by JPYS, thus revealing the mechanism of JPYS in correcting anemia in CKD. Experimental CKD rats with anemia were induced by 5/6 nephrectomy. Rats were administrated orally with high dose (6.0 g/kg/d) and low dose (1.5 g/kg/d) of JPYS for 90 days. Serum hepcidin level was determined to evaluate iron homeostasis. The protein expressions of HIF-2α, erythropoietin (EPO), ferritin, and ferroportin (FPN) and the phosphorylation level of extracellular signal-regulated kinase 1/2 (ERK1/2) were detected by Western blot. The results showed that JPYS treatment significantly ameliorated kidney function by reducing increased levels of blood urea nitrogen (BUN), serum creatinine (Scr), and urine protein (UPRO). Periodic acid-Schiff (PAS) and Masson staining observation showed that the renal pathological damage was restored in JPYS-treated CKD rats. In parallel, JPYS markedly improved CKD anemia through upregulation of red blood cell (RBC), hemoglobin (HGB), and hematocrit (HCT). JPYS stimulated EPO and HIF-2α protein expressions in both the kidney and liver of CKD rats. Furthermore, JPYS induced the phosphorylation of ERK1/2 protein. In addition, JPYS regulated protein expression of ferritin and FPN in both the liver and spleen of CKD rats and the serum level of hepcidin. In conclusion, JPYS induces the expression of EPO through ERK-mediated HIF-2α protein accumulation and regulates systemic iron recycling, supporting its role in promoting erythropoiesis and improvement of anemia in CKD.

Project description:San-Huang-Yi-Shen capsule (SHYS) has been used in the treatment of diabetic nephropathy (DN) in clinic. However, the mechanisms of SHYS on DN remain unknown. In this study, we used a high-fat diet (HFD) combined with streptozotocin (STZ) injection to establish a DN rat model. Next, we used 16S rRNA sequencing and untargeted metabolomics to study the potential mechanisms of SHYS on DN. Our results showed that SHYS treatment alleviated the body weight loss, hyperglycemia, proteinuria, pathological changes in kidney in DN rats. SHYS could also inhibite the oxidative stress and inflammatory response in kidney. 16S rRNA sequencing analysis showed that SHYS affected the beta diversity of gut microbiota community in DN model rats. SHYX could also decrease the Firmicutes to Bacteroidetes (F to B) ratio in phylum level. In genus level, SHYX treatment affected the relative abundances of Lactobacillus, Ruminococcaceae UCG-005, Allobaculum, Anaerovibrio, Bacteroides and Candidatus_Saccharimonas. Untargeted metabolomics analysis showed that SHYX treatment altered the serum metabolic profile in DN model rats through affecting the levels of guanidineacetic acid, L-kynurenine, prostaglandin F1α, threonine, creatine, acetylcholine and other 21 kind of metabolites. These metabolites are mainly involved in glycerophospholipid metabolism, tryptophan metabolism, alanine, aspartate and glutamate metabolism, arginine biosynthesis, tricarboxylic acid (TCA) cycle, tyrosine metabolism, arginine and proline metabolism, arginine and proline metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, phenylalanine metabolism, and D-glutamine and D-glutamate metabolism pathways. Spearman correlation analysis showed that Lactobacillus, Candidatus_Saccharimonas, Ruminococcaceae UCG-005, Anaerovibrio, Bacteroides, and Christensenellaceae_R-7_group were closely correlated with most of physiological data and the differential metabolites following SHYS treatment. In conclusion, our study revealed multiple ameliorative effects of SHYS on DN including the alleviation of hyperglycemia and the improvement of renal function, pathological changes in kidney, oxidative stress, and the inflammatory response. The mechanism of SHYS on DN may be related to the improvement of gut microbiota which regulates arginine biosynthesis, TCA cycle, tyrosine metabolism, and arginine and proline metabolism.

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Jian-Pi-Yi-Shen Formula Ameliorates Oxidative Stress, Inflammation, and Apoptosis by Activating the Nrf2 Signaling in 5/6 Nephrectomized Rats.

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