Nanocapsules With Naringin And Naringenin Affect Hepatic and Renal Energy Metabolism Without Altering Serum Markers of Toxicity in Rats

Naringin and naringenin are flavonoids found in citrus fruits and have several health benefits, however these compounds are susceptible to degradation, limiting their therapeutic application. To solve this problem, an alternative is to incorporate them into nanocapsules. The aim of this work was to evaluate the toxicity of these nanocapsules against renal and hepatic serum markers and also on the activities of pyruvate kinase, Mg2+-ATPase, and creatine kinase. Nanocapsules containing naringin and naringenin, nanocapsules without the active compounds and the compounds in their free form were administered orally, once a day, for 28 days. After treatment, the serum levels of hepatic and renal markers were not altered, nor the activities of pyruvate kinase tissue, however, the treatment of nanocapsules with flavonoids increased the activities of mitochondrial creatine kinase in the kidney and hepatic Mg2+-ATPase. Thus, renal and hepatic serum markers, which are normally used as indicators of toxicity, did not change after the period of administration of the nanoparticles. However, the activities of important enzymes of the energy metabolism in these organs were affected. Our findings reinforce that nanomaterial testing for toxicity needs to go beyond traditional methods to ensure the safe use of nanoparticles for therapeutic purposes.

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

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.

Renal energy metabolism and sodium reabsorption after 2,4-dinitrophenol administration

2,4-Dinitrophenol (DNP) (10 mg/kg body wt i.v.) increased renal cortical and outer medullary heat production rates and oxygen consumption by 70–90% in anesthetized dogs over a 90-min observation period without exerting any natriuretic effect. To examine whether DNP inhibited proximal reabsorption and increased distal delivery, ethacrynic acid (3 mg/kg body wt) was infused during maximal DNP effect. Sodium reabsorption fell by 14 +/- 6% in the cortex and 55 +/- 8% in the outer medulla, not significantly different from control experiments without DNP. Conversely, after ethacrynic acid administration, DNP had no additional natriuretic effect. Since DNP did not stimulate renal anaerobic metabolism (no lactate release), the effect of DNP was examined during hypoxia induced by intravenous infusion of NaCN (0.2 mumol/kg body wt-min) until renal metabolic rates fell. Subsequent infusion of DNP reduced tubular sodium reabsorption from 90 +/- 2 to 78 +/- 6%. Thus, DNP may raise renal metabolic rates by 70–90% without inhibiting sodium reabsorption, but, under conditions of hypoxia, DNP reduces sodium reabsorption and increases sodium excretion.