ABSTRACT
Accumulation of uremic toxins, which exert deleterious effects in chronic kidney disease, is influenced by the intestinal environment; the microbiota contributes to the production of representative uremic toxins, including p-cresyl sulfate and indoxyl sulfate. Canagliflozin is a sodium-glucose cotransporter (SGLT) 2 inhibitor, and it also exerts a modest inhibitory effect on SGLT1. The inhibition of intestinal SGLT1 can influence the gastrointestinal environment. We examined the effect of canagliflozin on the accumulation of uremic toxins in chronic kidney disease using adenine-induced renal failure mice. Two-week canagliflozin (10 mg/kg po) treatment did not influence the impaired renal function; however, it significantly reduced the plasma levels of p-cresyl sulfate and indoxyl sulfate in renal failure mice (a 75% and 26% reduction, respectively, compared with the vehicle group). Additionally, canagliflozin significantly increased cecal short-chain fatty acids in the mice, suggesting the promotion of bacterial carbohydrate fermentation in the intestine. Analysis of the cecal microbiota showed that canagliflozin significantly altered microbiota composition in the renal failure mice. These results indicate that canagliflozin exerts intestinal effects that reduce the accumulation of uremic toxins including p-cresyl sulfate. Reduction of accumulated uremic toxins by canagliflozin could provide a potential therapeutic option in chronic kidney disease.
Subject(s)
Canagliflozin/pharmacology , Gastrointestinal Microbiome/drug effects , Renal Insufficiency, Chronic/drug therapy , Toxins, Biological/blood , Animals , Disease Models, Animal , Gastrointestinal Tract/drug effects , Male , Mice, Inbred C57BL , Renal Insufficiency, Chronic/blood , Sodium-Glucose Transporter 2 Inhibitors/pharmacology , Toxins, Biological/pharmacology , Uremia/blood , Uremia/drug therapyABSTRACT
Mitochondrial dysfunction increases oxidative stress and depletes ATP in a variety of disorders. Several antioxidant therapies and drugs affecting mitochondrial biogenesis are undergoing investigation, although not all of them have demonstrated favorable effects in the clinic. We recently reported a therapeutic mitochondrial drug mitochonic acid MA-5 (Tohoku J. Exp. Med., 2015). MA-5 increased ATP, rescued mitochondrial disease fibroblasts and prolonged the life span of the disease model "Mitomouse" (JASN, 2016). To investigate the potential of MA-5 on various mitochondrial diseases, we collected 25 cases of fibroblasts from various genetic mutations and cell protective effect of MA-5 and the ATP producing mechanism was examined. 24 out of the 25 patient fibroblasts (96%) were responded to MA-5. Under oxidative stress condition, the GDF-15 was increased and this increase was significantly abrogated by MA-5. The serum GDF-15 elevated in Mitomouse was likewise reduced by MA-5. MA-5 facilitates mitochondrial ATP production and reduces ROS independent of ETC by facilitating ATP synthase oligomerization and supercomplex formation with mitofilin/Mic60. MA-5 reduced mitochondria fragmentation, restores crista shape and dynamics. MA-5 has potential as a drug for the treatment of various mitochondrial diseases. The diagnostic use of GDF-15 will be also useful in a forthcoming MA-5 clinical trial.
Subject(s)
Indoleacetic Acids/pharmacology , Mitochondria/drug effects , Mitochondria/metabolism , Mitochondrial Diseases/metabolism , Mitochondrial Proton-Translocating ATPases/metabolism , Phenylbutyrates/pharmacology , Protein Multimerization/drug effects , Adenosine Triphosphate/metabolism , Animals , Biomarkers , Cell Line , Cell Survival/drug effects , DNA, Mitochondrial , Disease Models, Animal , Fibroblast Growth Factors/metabolism , Fibroblasts/metabolism , Growth Differentiation Factor 15/metabolism , Humans , Membrane Potential, Mitochondrial/drug effects , Mice , Mitochondria/genetics , Mitochondrial Diseases/diagnosis , Mitochondrial Diseases/drug therapy , Mitochondrial Diseases/genetics , Mitochondrial Dynamics/drug effects , Mitochondrial Proton-Translocating ATPases/chemistry , Multiprotein Complexes/metabolism , Mutation , Organelle Biogenesis , Prognosis , Protective Agents , Protein BindingABSTRACT
Renal fibrosis is closely related to chronic inflammation and is under the control of epigenetic regulations. Because the signaling of transforming growth factor-ß1 (TGF-ß1) and tumor necrosis factor-α (TNF-α) play key roles in progression of renal fibrosis, dual blockade of TGF-ß1 and TNF-α is desired as its therapeutic approach. Here we screened small molecules showing anti-TNF-α activity in the compound library of indole derivatives. 11 out of 41 indole derivatives inhibited the TNF-α effect. Among them, Mitochonic Acid 35 (MA-35), 5-(3, 5-dimethoxybenzyloxy)-3-indoleacetic acid, showed the potent effect. The anti-TNF-α activity was mediated by inhibiting IκB kinase phosphorylation, which attenuated the LPS/GaIN-induced hepatic inflammation in the mice. Additionally, MA-35 concurrently showed an anti-TGF-ß1 effect by inhibiting Smad3 phosphorylation, resulting in the downregulation of TGF-ß1-induced fibrotic gene expression. In unilateral ureter obstructed mouse kidney, which is a renal fibrosis model, MA-35 attenuated renal inflammation and fibrosis with the downregulation of inflammatory cytokines and fibrotic gene expressions. Furthermore, MA-35 inhibited TGF-ß1-induced H3K4me1 histone modification of the fibrotic gene promoter, leading to a decrease in the fibrotic gene expression. MA-35 affects multiple signaling pathways involved in the fibrosis and may recover epigenetic modification; therefore, it could possibly be a novel therapeutic drug for fibrosis.
Subject(s)
Indoles/pharmacology , Kidney Diseases/metabolism , Kidney Diseases/pathology , Signal Transduction/drug effects , Transforming Growth Factor beta1/metabolism , Tumor Necrosis Factor-alpha/metabolism , Animals , Cell Line , Disease Models, Animal , Extracellular Matrix/metabolism , Fibrosis , Hepatitis/drug therapy , Hepatitis/etiology , Hepatitis/metabolism , Hepatitis/pathology , Histones/metabolism , Humans , I-kappa B Kinase/metabolism , Kidney Diseases/drug therapy , Kidney Diseases/etiology , Lipopolysaccharides/adverse effects , Male , Methylation , Mice , Models, Biological , Phosphorylation/drug effects , Smad3 Protein/metabolismABSTRACT
Previously, we showed that the growth of chicks fed a diet containing 43% whole-grain paddy rice and 10% soybean oil was retarded relative to a control group fed a corn-based diet containing 6% soybean oil. However, feeding chicks with 43% whole-grain paddy rice containing 6% soybean oil resulted in normal growth. It is possible that the observed growth retardation was caused by the high soybean oil content or resulted from the combination of whole-grain paddy rice and the high level of soybean oil which was added to the diet to maintain the overall energy content. The present study was therefore carried out to identify the reasons for the observed growth retardation. Thirty-six chicks (0-day-old) were divided into six equal-sized groups that were fed one of the following six experimental diets ad libitum for 28 d: two kinds of dehulled rice-based diets containing 5% or 10% soybean oil (DS5% or DS10%), another three whole-grain paddy rice-based diets containing 10% soybean oil, corn oil, or rendering oil (WS10%, WC10%, WR10%, respectively), and a WS10% diet supplemented with vitamin B12, methionine and ethoxyquin. The body weight gain of groups fed the WS10% and WC10% diets was significantly lower than the weight gain of birds fed the DS5% diet (control). In addition, the liver of birds fed the WS10% and WC10% diet exhibited significantly higher lipid peroxidation than that of the control group. In comparison, supplementation of the WS10% diet with vitamin B12, methionine and ethoxyquin dramatically improved growth and hepatic oxidation status. These results indicate that diets combining whole-grain paddy rice and high levels of soybean and corn oil adversely affect performance, presumably via lipid peroxidation in the liver.
