Chengshi Wang

Metabonomics revealed xanthine oxidase-induced oxidative stress and inflammation in the pathogenesis of diabetic nephropathy

AbstractDiabetic nephropathy (DN) is a serious complication of diabetes mellitus (DM), which is a major public health problem in the world. To reveal the metabolic changes associated with DN, we analyzed the serum, urine, and renal extracts obtained from control and streptozotocin (STZ)-induced DN rats by 1H NMR-based metabonomics and multivariate data analysis. A significant difference between control and DN rats was revealed in metabolic profiles, and we identified several important DN-related metabolites including increased levels of allantoin and uric acid (UA) in the DN rats, suggesting that disturbed purine metabolism may be involved in the DN. Combined with conventional histological and biological methods, we further demonstrated that xanthine oxidase (XO), a key enzyme for purine catabolism, was abnormally activated in the kidney of diabetic rats by hyperglycemia. The highly activated XO increased the level of intracellular ROS, which caused renal injury by direct oxidative damage to renal cells, and indirect inducing inflammatory responses via activating NF-κB signaling pathway. Our study highlighted that metabonomics is a promising tool to reveal the metabolic changes and the underlying mechanism involved in the pathogenesis of DN. Graphical AbstractIn this study, we performed 1H NMR-based metabonomic to analyze the serum, urine, and renal extracts in a rat model of diabetic nephropathy (DN), and identified the disturbed purine metabolism and its underlying xanthine oxidase induced oxidative stress and inflammation was involved in the pathogenesis of DN

1H NMR-based metabonomic analysis of serum and urine in a nonhuman primate model of diabetic nephropathy

Diabetic nephropathy (DN) is a serious metabolic disease, and comprehensive understanding of its complex mechanism will help in preventing the onset and progression of DN. To reveal the systemic metabolic changes associated with renal injury, we performed 1H NMR-based metabonomic and multivariate analyses to analyze serum and urine obtained from a nonhuman primate model of DN. Our results indicated that DN monkeys exhibited a distinct metabolic profile, including higher levels of VLDL/LDL, lipids, unsaturated lipids, uric acid, allantoin, fumarate and hippurate, as well as lower levels of HDL, alanine, glutamate, pyruvate, formate, tyrosine, histidine and NAD+. The disturbed metabolic pathways were further identified, including NAD+ metabolism, purine metabolism, oxidative stress, lipid metabolism, and renal tubular reabsorption. This study highlights that NMR-based metabonomics provides insight into the underlying pathways in the pathogenesis and progression of DN at the metabolic level.

A preclinical evaluation of alternative site for islet allotransplantation

The bone marrow cavity (BMC) has recently been identified as an alternative site to the liver for islet transplantation. This study aimed to compare the BMC with the liver as an islet allotransplantation site in diabetic monkeys. Diabetes was induced in Rhesus monkeys using streptozocin, and the monkeys were then divided into the following three groups: Group1 (islets transplanted in the liver with immunosuppressant), Group 2 (islets transplanted in the tibial BMC), and Group 3 (islets transplanted in the tibial BMC with immunosuppressant). The C-peptide and blood glucose levels were preoperatively measured. An intravenous glucose tolerance test (IVGTT) was conducted to assess graft function, and complete blood cell counts were performed to assess cell population changes. Cytokine expression was measured using an enzyme-linked immune sorbent assay (ELISA) and MILLIPLEX. Five monkeys in Group 3 exhibited a significantly increased insulin-independent time compared with the other groups (Group 1: 78.2 ± 19.0 days; Group 2: 58.8 ± 17.0 days; Group 3: 189.6 ± 26.2 days) and demonstrated increases in plasma C-peptide 4 months after transplantation. The infusion procedure was not associated with adverse effects. Functional islets in the BMC were observed 225 days after transplantation using the dithizone (DTZ) and insulin/glucagon stains. Our results showed that allogeneic islets transplanted in the BMC of diabetic Rhesus monkeys remained alive and functional for a longer time than those transplanted in the liver. This study was the first successful demonstration of allogeneic islet engraftment in the BMC of non-human primates (NHPs).

MSCs promote the development and improve the function of neonatal porcine islet grafts

Deficient insulin secretion caused by immaturity is the predominant disadvantage of neonatal porcine islets (NPIs) when they serve as a source for islet xenotransplantation. We hypothesize that the transplantation of NPIs with a combination of mesenchymal stem cells (MSCs) can accelerate NPI maturation and improve the engraftment and function of NPIs. After indirect coculturing with monkey MSCs over 21 d, insulin secretion and the expression of regulatory genes relevant to development were assessed in NPIs. NPIs alone or in combination with allogeneic MSCs were intraportally transplanted into diabetic monkeys. Glycemic control was monitored, and graft function was evaluated. Our results suggest that MSCs benefit both the development and proliferation of NPIs in the coexisting systems in vitro and in vivo. These effects are dependent on platelet‐derived growth factor receptor‐a and are relevant to the inhibition of downstream target Notch1 signaling and the activation of PI3K/protein kinase B signaling.—He, S., Wang, C., Du, X., Chen, Y., Zhao, J., Tian, B., Lu, H., Zhang, Y., Liu, J., Yang, G., Li, L., Li, H., Cheng, J., Lu, Y. MSCs promote the development and improve the function of neonatal porcine islet grafts. FASEB J. 32, 3242–3253 (2018). www.fasebj.org

GLP-1 receptor agonist ameliorates obesity-induced chronic kidney injury via restoring renal metabolism homeostasis

Increasing evidence indicates that obesity is highly associated with chronic kidney disease (CKD). GLP-1 receptor (GLP-1R) agonist has shown benefits on kidney diseases, but its direct role on kidney metabolism in obesity is still not clear. This study aims to investigate the protection and metabolic modulation role of liraglutide (Lira) on kidney of obesity. Rats were induced obese by high-fat diet (HFD), and renal function and metabolism changes were evaluated by metabolomic, biological and histological methods. HFD rats exhibited systemic metabolic disorders such as obesity, hyperlipidemia and impaired glucose tolerance, as well as renal histological and function damages, while Lira significantly ameliorated these adverse effects in HFD rats. Metabolomic data showed that Lira directly reduced renal lipids including fatty acid residues, cholesterol, phospholipids and triglycerides, and improved mitochondria metabolites such as succinate, citrate, taurine, fumarate and nicotinamide adenine dinucleotide (NAD+) in the kidney of HFD rats. Furthermore, we revealed that Lira inhibited renal lipid accumulation by coordinating lipogenic and lipolytic signals, and partly rescued renal mitochondria function via Sirt1/AMPK/PGC1α pathways in HFD rats. This study suggested that Lira alleviated HFD-induced kidney injury at least partly via directly restoring renal metabolism, thus GLP-1R agonist is a promising therapy for obesity-associated CKD.

Gene expression profile of vascular ischemia-reperfusion injury in rhesus monkeys

UNLABELLED The vascular system particularly endothelium is sensitive to ischemia-reperfusion (I/R) injury, which is a big challenge in surgical practices and many vascular disorders. In the present study, we reported the global gene expression changes in a 2-h ischemia and 4-h reperfusion injury induced in the hind limb vessels of rhesus monkeys (Macaca mulatta) using microarray technique. RESULTS The histological results showed abnormal morphology of endothelial cells after 2-h ischemia and the hematological detection found slightly extension of coagulation time after I/R treatment. Furthermore, we found distinct alterations in gene expression patterns during I/R process. These identified genes are mostly involved in inflammation, immune response, apoptosis, and cell stress signaling pathways. The significantly up-regulated genes included IL-6, regulator of G-protein signaling 8, selectin E, and metallothionein 2A, et al. Whist, the robustly down-regulated genes included NECAP endocytosis associated 2, transglutaminase 2, and fibronectin 1, et al. CONCLUSION Our results indicate that inflammation, primarily characterized by gene expression changes of cytokines and chemokines is the most important event in the early stage of I/R injury in blood vessels.

GLP-1 receptor agonist ameliorates obesity-induced chronic kidney injury via restoring renal lipid and energy metabolism homeostasis: revealed by metabolomics

Increasing evidence indicate that obesity is highly associated with chronic kidney disease (CKD).GLP-1 receptor (GLP-1R) agonist has shown benefits on kidney diseases, but its direct role on kidney metabolism in obesity is still not clear. This study aims to investigate the protection and metabolic modulation role of liraglutide (Lira) on kidney of obesity. Rats were induced obese by high-fat diet (HFD), and renal function and metabolism changes were evaluated by metabolomic, biological and histological methods. HFD rats exhibited metabolic disorders including elevated body weight, hyperlipidemia and impaired glucose tolerance, and remarkable renal injuries including declined renal function and inflammatory/fibrotic changes, whereas Lira significantly ameliorated these adverse effects in HFD rats. Metabolomic data showed that Lira reduced renal lipids including fatty acid residues, cholesterol, phospholipids and triglycerides, and improved mitochondria metabolites such as succinate, citrate, taurine, fumarate and NAD+ in the kidney of HDF rats. Furthermore, we revealed that Lira inhibited renal lipid accumulation by coordinating lipogenic and lipolytic signals, and rescued renal mitochondria function via Sirt1/AMPK/PGC1α pathways in HDF rats. This study suggested that Lira alleviated HFD-induced kidney injury via directly restoring renal lipid and energy metabolism, and GLP-1 receptor agonist is a promising therapy for obesity-associated CKD.

Glucocorticoid treatment facilitates development of a metabolic syndrome in ovariectomized Macaca Mulatta fed a high fat diet

HighlightsWe reported for the first time that the endocrine and physiological changes in response to chronic and high dose of GCs in non‐human primates, and the effects of withdrawal of a long‐term treatment, which led to recovery from metabolic disorders.We used ovariectomized monkeys to mimic the situation of perimenopausal and postmenopausal women, and might be used as potential models of Cushing’s syndrome or MetS in non‐human primates.The lipid and glucose related factors including leptin and GLUT4 play important roles in the GCs effect. Abstract Metabolic syndrome (MetS) is characterized by a cluster of key features, which include abdominal obesity, insulin resistance, hypertension, and dyslipidemia. The aim of this study was to assess the impact of elevated glucocorticoid levels on the development of MetS in middle‐aged female rhesus monkeys (Macaca Mulatta) after ovariectomy. Six female ovariectomized rhesus monkeys (9–13 years) were randomly assigned to either a control group (normal diet, n = 3) or a group in which MetS was facilitated (n = 3). The MetS group fed with HFD (15% fat) and received oral prednisone acetate treatment (50 mg/day). After 24 months, the GCs treatment was withdrawn with continuation of high‐fat feeding for a further 12 months. After 24 months, the MetS group displayed a significant increase in body weight and abdominal circumference. Additionally, the MetS animals displayed abnormal serum lipids, insulin resistance and impaired glucose tolerance. Histology of liver biopsies indicated marked accumulation of lipid droplets in hepatocytes of MetS animals. Withdrawal of GCs treatment led to recovery from above‐mentioned metabolic disorders. Whereas GCs treatment increased leptin expression, it lowered expression of adiponectin and other factors in adipose tissue. Expression of Hydroxy‐steroid dehydrogenase‐1 and glucose transporter type‐4 in the livers of MetS animals were reduced. We conclude that in the context of high fat diet, high levels of exogenous GCs contribute to the development of MetS in non‐human primates.