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Enarodustat, hypoxia-inducible factor stabilizer, counteracts the diabetic renal energy metabolism alterations in streptozotocin-induced diabetic rats

ABSTRACT: We analyzed the effects of enarodustat (JTZ-951; HIF stabilizer) on renal energy metabolism in streptozotocin-induced diabetic rat model. Transcriptome analysis of renal cortex revealed that genes related to fatty acid metabolism and amino acid metabolism were upregulated in diabetes and downregulated by enarodustat, whereas genes related to glucose metabolism were upregulated by enarodustat. Thus, HIF stabilization counteracts the renal energy metabolism alterations occurring in the early stages of diabetic kidney disease.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE131221 | GEO | 2020/05/14

REPOSITORIES: GEO

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Enarodustat, a hypoxia-inducible factor stabilizer, counteracts the diabetic renal energy metabolism alterations in the early stages of diabetic kidney disease

Project description:We analyzed the effects of enarodustat (JTZ-951; HIF stabilizer) on renal energy metabolism in alloxan-induced diabetic mouse model. Transcriptome analysis of renal tissue revealed that genes related to fatty acid metabolism were upregulated in diabetes, whereas genes related to glucose metabolism were upregulated by enarodustat. In addition, genes related to amino acid metabolism were upregulated by diabetes and downregulated by enarodustat. Thus, HIF stabilization counteracts the renal energy metabolism alterations occurring in the early stages of diabetic kidney disease.

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Enarodustat, hypoxia-inducible factor stabilizer, counteracts the diabetic renal energy metabolism alterations in streptozotocin-induced diabetic rats

Project description:Enarodustat, hypoxia-inducible factor stabilizer, counteracts the diabetic renal energy metabolism alterations in streptozotocin-induced diabetic rats

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Project description:Enarodustat, a hypoxia-inducible factor stabilizer, counteracts the diabetic renal energy metabolism alterations in the early stages of diabetic kidney disease

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Project description:diabetes, mouse models, diabetic nephropathy, streptozotocin db/db Keywords: other

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2012-05-30 | GSE38138 | GEO

Hepatic gene expression in streptozotocin-induced diabetic mice fed a phloridzin diet

Project description:Phloridzin is a dihydrochalcone typically contained in apples. A diet containing 0.5 % phloridzin significantly improves hyperglycemia but not hypoinsulinemia and tissue lipid peroxidation in streptozotocin (STZ)-induced diabetic mice after 14 days. The phloridzin diet has no effect on the alteration of hepatic gene expression in STZ-induced diabetic mice. A quantitative RT-PCR analysis showed a reversal of the STZ induction of the sodium/glucose cotransporter gene Sglt1 and the drug-metabolizing enzyme genes Cyp2b10 and Ephx1 in the small intestine of mice fed a 0.5% phloridzin diet. These mice also showed a reversal of the STZ-mediated renal induction of the glucose-regulated facilitated glucose transporter gene Glut2. Dietary phloridzin improved the abnormal elevations in blood glucose level and the overexpression of Sglt1, Cyp2b10 and Ephx1 in the small intestine of STZ-induced diabetic mice. Six-week-old male mice were divided into 4 groups of 6 mice each, housed in groups of 3 per cage. After 1 week mice were intraperitoneally injected with STZ. Mice (n=6) in the untreated control group did not receive any treatment. After 1 week, 18 mice showing non-fasting blood glucose levels of 330-590 mg/dL were divided into 3 groups: one group was fed with AIN93G only (control group), the others with an AIN93G diet containing 0.1% or 0.5% phloridzin (Funakoshi, Tokyo, Japan) for 2 weeks.

2012-05-29 | E-GEOD-38138 | biostudies-arrayexpress

Deficiency of C3a receptor attenuates the development of diabetic nephropathy (Diabetic Group)

Project description:Diabetic nephropathy (DN) is the leading cause of chronic kidney disease and end-stage renal disease. Emerging evidence suggests that complement activation is involved in the pathogenesis of DN. The aim of this study was to investigate the pathogenic role of C3a and C3a receptor (C3aR) in DN. The expression of C3aR was examined in the renal specimen of DN patients. Using a C3aR gene knockout mice (C3aR-/-), we evaluated kidney injury in diabetic mice. The mouse gene expression microarray was performed to further explore the pathogenic role of C3aR. Then the underlying mechanism was investigated in vitro with macrophage treated with C3a. Compared with normal controls, the renal expression of C3aR was significantly increased in DN patients. C3aR-/- diabetic mice developed less severe diabetic renal damage compared with WT diabetic mice, exhibiting significantly lower level of albuminuria and milder renal pathological injury. Microarray profiling uncovered significantly suppressed inflammatory responses and T cell adaptive immunity in C3aR-/- diabetic mice compared with WT diabetic mice and this result was further verified by immunohistochemical staining of renal CD4+, CD8+ T cells and macrophages infiltration. In vitro study demonstrated C3a can enhance macrophages secreted cytokines which could induce inflammatory responses and differentiation of T cell lineage. In conclusion, C3aR deficiency could attenuate diabetic renal damage through suppressing inflammatory responses and T cell adaptive immunity, possibly by influencing macrophages secreted cytokines. Thus, C3aR may be a promising therapeutic target for DN.

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Sirtuin 5 Reduces Malonylation in Non-mitochondrial Metabolic Pathways in Diabetic Kidney Disease

Project description:Early diabetic kidney disease (DKD) is marked by dramatic metabolic reprogramming due to nutrient excess, mitochondrial dysfunction, and increased renal energy requirements from hyperfiltration. We hypothesized that changes in metabolism in DKD may be regulated by Sirtuin 5 (SIRT5), a deacylase that removes post-translational modifications derived from acyl-coenzyme A and has been demonstrated to regulate numerous metabolic pathways. We found decreased malonylation in kidney cortex (~80% proximal tubules) of type 2 diabetic BKS db/db mice, associated with increased SIRT5 expression. Proteomics analysis of malonylated peptides found that proteins with significantly decreased malonylated lysines in the db/db cortex were enriched in non-mitochondrial metabolic pathways: glycolysis and peroxisomal fatty acid oxidation (FAO). To confirm relevance of these findings in human disease, we analyzed diabetic kidney transcriptomic data from a cohort of Southwestern American Indians which revealed tubulointerstitial specific increase in Sirt5 expression. Overexpression of SIRT5 in cultured human proximal tubules demonstrated increased aerobic glycolysis with reduced mitochondrial metabolism, and conversely with decreased SIRT5 expression, there was reduced glycolysis and increased mitochondrial metabolism. These findings suggest that SIRT5 may lead to differential nutrient partitioning and utilization in DKD. Our findings highlight a previously unrecognized role for SIRT5 in metabolic reprogramming in DKD.

2023-06-26 | PXD037819 | panorama

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