Abstract: TH-PO888
Enarodustat, Hypoxia-Inducible Factor Stabilizer, Counteracts the Diabetic Renal Energy Metabolism Alterations Occurring in the Early Stages of Diabetic Kidney Disease
Session Information
- Diabetic Kidney Disease: Basic - I
November 07, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 601 Diabetic Kidney Disease: Basic
Authors
- Hasegawa, Sho, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
- Tanaka, Tetsuhiro, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
- Saito, Tomoyuki, JT Central Pharmaceutical Research Institute, Takatsuki, Osaka-Fu, Japan
- Fukui, Kenji, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
- Wakashima, Takeshi, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
- Nangaku, Masaomi, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
Background
Hypoxia-inducible factor stabilizers (HIF stabilizers) increase endogenous erythropoietin production and serve as novel therapeutic agents against anemia in chronic kidney disease. Although HIF induces the expression of various genes related to energy metabolism, the effects of HIF stabilizers on energy metabolism in renal tissue, especially in pathological conditions, remain obscure. Here, we analyzed the effects of enarodustat (JTZ-951; HIF stabilizer) on renal energy metabolism in streptozotocin (STZ)-induced diabetic rat model.
Methods
We divided the rats into three groups; group A (Sham), B (DKD) and C (DKD+enarodustat). First, vehicle (n = 5; group A) or 65 mg/kg of STZ (n = 19) were intravenously administered into rats 7 days before grouping. We selected the rats for group B and C (n = 7, for each group) by matching blood glucose and body weight of STZ-induced diabetic rats. Group A and B were given normal feed, while group C was given the feed mixed with 0.01% (w/w) of enarodustat. Kidney samples were collected 14 days after grouping. We conducted the transcriptome and metabolome analysis of these rats’ renal cortical tissue.
Results
Transcriptome analysis of renal cortex revealed that fatty acid and amino acid metabolism were upregulated by diabetes and downregulated by enarodustat, while glucose metabolism was upregulated by enarodustat, showing that enarodustat reversed the renal metabolic alterations induced by diabetes. Metabolome data indicated accumulation of glucose and tricarboxylic acid (TCA) cycle metabolites and a reduction of amino acid concentration in diabetic renal cortex, while these metabolic alterations were mitigated by enarodustat. Moreover, enarodustat alleviated the accumulation of glutathione disulfide (GSSG) observed in diabetic kidney, indicating that enarodustat relieves the oxidative stress in diabetic kidney.
Conclusion
Enarodustat, HIF stabilizer, counteracts the diabetic renal energy metabolism alterations occurring in the early stages of diabetic kidney disease. Our study suggests that HIF stabilization may serve as a potential intervention targeting dysregulated energy metabolism of diabetic kidneys.
Funding
- Government Support - Non-U.S.