SO049HYPOXIA INDUCIBLE FACTOR-PROLYL HYDROXYLASE (HIF-PH) INHIBITION COUNTERACTS THE RENAL ENERGY METABOLISM ALTERATIONS IN THE EARLY STAGES OF DIABETIC KIDNEY DISEASE

Abstract

Abstract Background and Aims Hypoxia inducible factor (HIF)-prolyl hydroxylase (PH) inhibitors (also known as HIF stabilizers) increase endogenous erythropoietin production and serve as novel therapeutic agents against anemia in chronic kidney disease. Considering that HIF induces the expression of various genes, HIF stabilizers might have pleiotropic effects on the progression of kidney diseases as well as improvement in anemia. Interestingly, HIF induces the metabolic reprogramming from tricarboxylic acid (TCA) cycle to glycolysis as an adaptive response to hypoxia. However, it remains obscure how the metabolic reprogramming in renal tissue by HIF stabilization affects the pathophysiology of kidney diseases. Previous studies have shown accumulation of glucose and TCA cycle metabolites in diabetic renal tissue, which might be related to the progression of diabetic kidney disease (DKD). We hypothesized that HIF stabilization might reverse these metabolism alterations and conducted a proof-of-concept study using enarodustat (JTZ-951), an oral HIF-PH inhibitor. Method We utilized the streptozotocin-induced diabetic rat and alloxan-induced diabetic mouse models. Animals were divided into three groups: Control (normal animals eating normal food), DKD (diabetic animals eating normal food) and DKD+enarodustat (diabetic animals eating food mixed with enarodustat). Blood, urine and kidney samples were collected two weeks after grouping. Metabolism status in renal tissue were compared between groups from transcriptome and metabolome perspectives. Results Although plasma creatinine levels were not different between groups, enarodustat tended to reverse diabetic renal changes such as urinary albumin excretion, glomerulomegaly and glomerular basement membrane thickening (Figure 1). Transcriptome analysis has revealed that enarodustat counteracts the diabetic renal metabolism alterations; fatty acid and amino acid metabolisms were upregulated in diabetic renal tissue and downregulated by enarodustat, while glucose metabolism was upregulated by enarodustat. These symmetric metabolism alterations were confirmed by metabolome analysis (Figure 2); glycolysis and TCA cycle metabolites were accumulated, and amino acids were reduced in diabetic renal tissue, while these metabolism alterations were mitigated by enarodustat. Moreover, enarodustat alleviated the accumulation of glutathione disulfide (GSSG) in diabetic renal tissue and thus showed higher glutathione (GSH)/GSSG ratio, which suggested that enarodustat relieved oxidative stress in DKD. Conclusion HIF stabilization counteracts the renal energy metabolism alterations in the early stages of DKD, in association with the improvement in urinary albumin excretion and renal pathological abnormalities. Our study suggests that HIF stabilization may serve as a potential intervention targeting dysregulated energy metabolism of diabetic kidneys.