RESUMO
BACKGROUND: Hypoxia-inducible factor (HIF) transcriptional system plays a central role in cellular adaptation to low oxygen levels. Preconditional activation of HIF and/or expression of its individual target gene products leading to cytoprotection have been well established in hypoxic/ischemic renal injury. Increasing evidence indicate HIF activation is involved in hypoxic/ischemic postconditioning of heart, brain and kidney. Very few studies evaluated the potential benefits of postischemia HIF activation in renal injury employing a pharmacological agent. We hypothesized that postischemia augmentation of HIF activation with a pharmacological agent would protect renal ischemia/reperfusion injury. For this, TRC160334, a novel HIF hydroxylase inhibitor, was used. METHODS: TRC160334, a novel HIF hydroxylase inhibitor, was synthesized. Ability of TRC160334 for stabilization of HIF-α and consequent HIF activation was evaluated in Hep3B cells. Efficacy of TRC160334 was evaluated in a rat model of ischemia/reperfusion-induced AKI. Two different treatment protocols were employed, one involved treatment with TRC160334 before onset of ischemia, the other involved treatment after the reperfusion of kidneys. RESULTS: TRC160334 treatment results in stabilization of HIF-α leading to HIF activation in Hep3B cells. Significant reduction in renal injury was observed by both treatment protocols and remarkable reduction in serum creatinine (23 and 71% at 24 and 48 h, respectively, p < 0.01) was observed with TRC160334 treatment applied after reperfusion. Urine output was significantly improved up to 24 h by both treatment protocols. CONCLUSION: The data presented here provide pharmacologic evidence for postischemia augmentation of HIF activation by TRC160334 as a promising and clinically feasible strategy for the treatment of renal ischemia/reperfusion injury.
Assuntos
Injúria Renal Aguda/tratamento farmacológico , Glicina/análogos & derivados , Compostos Heterocíclicos com 3 Anéis/farmacologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Creatinina/sangue , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica , Glicina/farmacologia , Humanos , Prolina Dioxigenases do Fator Induzível por Hipóxia , Masculino , Modelos Biológicos , Proteínas Nucleares/antagonistas & inibidores , Pró-Colágeno-Prolina Dioxigenase/antagonistas & inibidores , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/tratamento farmacológico , Fatores de TempoRESUMO
Chronic overnutrition and modern lifestyles are causing a worldwide epidemic of obesity and associated comorbidities, which is creating a demand to identify underlying biological mechanisms and to devise effective treatments. In rats receiving a high-fat diet (HFD), we analyzed the effects of a 4-wk administration of a novel functional analog of iodothyronines, TRC150094 (TRC). HFD-TRC rats exhibited increased energy expenditure (+24% vs. HFD rats; P<0.05) and body weight (BW) gain comparable to that of standard chow-fed (N) rats [N, HFD, and HFD-TRC rats, +97 g, +140 g (P<0.05 vs. N), and +98 g (P<0.05 vs. HFD)]. HFD-TRC rats had significantly less visceral adipose tissue (vs. HFD rats) and exhibited altered metabolism in two major tissues that are very active metabolically. In liver, mitochondrial fatty acid import and oxidation were increased (+56 and +32%, respectively; P<0.05 vs. HFD rats), and consequently the hepatic triglyceride content was lower (-35%; P<0.05 vs. HFD rats). These effects were independent of the AMP-activated protein kinase-acetyl CoA-carboxylase-malonyl CoA pathway but involved sirtuin 1 activation. In skeletal muscle, TRC induced a fiber shift toward the oxidative type in tibialis anterior muscle, increasing its capacity to oxidize fatty acids. HFD-TRC rats had lower (vs. HFD rats) plasma cholesterol and triglyceride concentrations. If reproduced in humans, these results will open interesting possibilities regarding the counteraction of metabolic dysfunction associated with ectopic/visceral fat accumulation.
Assuntos
Adiposidade/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Ácidos Graxos/metabolismo , Tironinas/farmacologia , Animais , Western Blotting , Peso Corporal/efeitos dos fármacos , Carnitina O-Palmitoiltransferase/metabolismo , Gorduras na Dieta/efeitos adversos , Ingestão de Alimentos/efeitos dos fármacos , Masculino , Obesidade/sangue , Obesidade/induzido quimicamente , Obesidade/metabolismo , Oxirredução/efeitos dos fármacos , Ratos , Ratos Wistar , Sirtuína 1/metabolismo , Tironinas/química , Tireotropina/sangue , Tiroxina/sangue , Triglicerídeos/sangue , Tri-Iodotironina/sangueRESUMO
A novel class of N-substituted 4-hydrazino piperidine derivatives were designed, synthesized and evaluated for DPP IV inhibition. The SAR studies on the N-substituted piperidine led to the discovery of compound 22e as a potent DPP IV inhibitor (IC(50) 88nM), which is highly selective over other peptidases. In vivo efficacy indicates that compound 22e stimulates insulin release in response to glucose load and improves glucose tolerance in n5-STZ and Zucker Diabetic Fatty (ZDF) rats.