RESUMEN
Diabetic nephropathy (DN) is a common cause of end-stage kidney disease (ESKD) all over the world. Sitagliptin, an inhibitor of DPP-IV plays a beneficial role in type 2 diabetic nephropathy. The purpose of this study was to explore the effect and mechanism of sitagliptin on renal injury in type 1 diabetic mice. Streptozotocin (STZ) induced type 1 diabetic mice were treated with oral administration of sitagliptin (15 mg/kg/ day) for 4 weeks. The results showed that sitagliptin treatment did not change the levels of blood glucose in STZ induced type 1 diabetic mice. Sitagliptin attenuates diabetic nephropathy by significantly inhibiting 24 h proteinuria, renal injury and fibrosis. Sitagliptin can inhibit the expression level of TGF-ß1 and the other related fibrosis factors in renal tissue of type 1 diabetic mice while delaying the progression of type 1 diabetic nephropathy. These results indicated that sitagliptin treatment is potentially a new strategy for treating type 1 diabetic nephropathy.
Asunto(s)
Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Nefropatías Diabéticas/prevención & control , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Fosfato de Sitagliptina/farmacología , Administración Oral , Animales , Glucemia/efectos de los fármacos , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Tipo 1/complicaciones , Hipoglucemiantes/farmacología , Masculino , Ratones , Proteinuria/prevención & control , Transducción de Señal/efectos de los fármacos , Proteínas Smad/metabolismo , Estreptozocina , Factor de Crecimiento Transformador beta1/genéticaRESUMEN
Diabetic nephropathy is characterized by persistent albuminuria, progressive decline in GFR, and secondary hypertension. MicroRNAs are dysregulated in diabetic nephropathy, but identification of the specific microRNAs involved remains incomplete. Here, we show that the peripheral blood from patients with diabetes and the kidneys of animals with type 1 or 2 diabetes have low levels of microRNA-25 (miR-25) compared with those of their nondiabetic counterparts. Furthermore, treatment with high glucose decreased the expression of miR-25 in cultured kidney cells. In db/db mice, systemic administration of an miR-25 agomir repressed glomerular fibrosis and reduced high BP. Notably, knockdown of miR-25 in normal mice by systemic administration of an miR-25 antagomir resulted in increased proteinuria, extracellular matrix accumulation, podocyte foot process effacement, and hypertension with renin-angiotensin system activation. However, excessive miR-25 did not cause kidney dysfunction in wild-type mice. RNA sequencing showed the alteration of miR-25 target genes in antagomir-treated mice, including the Ras-related gene CDC42. In vitro, cotransfection with the miR-25 antagomir repressed luciferase activity from a reporter construct containing the CDC42 3' untranslated region. In conclusion, these results reveal a role for miR-25 in diabetic nephropathy and indicate a potential novel therapeutic target for this disease.
Asunto(s)
Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Nefropatías Diabéticas/metabolismo , Regulación de la Expresión Génica , MicroARNs/genética , Albuminuria/metabolismo , Animales , Presión Sanguínea , Complicaciones de la Diabetes/metabolismo , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 2/genética , Nefropatías Diabéticas/genética , Progresión de la Enfermedad , Fibrosis/patología , Humanos , Hipertensión/complicaciones , Riñón/metabolismo , Glomérulos Renales/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , MicroARNs/metabolismo , Estrés Oxidativo , Podocitos/metabolismo , Proteinuria/metabolismo , Proteína de Unión al GTP cdc42/metabolismoRESUMEN
The aim of the present study was to investigate the influence of biotransformation of baicalin into baicalein towards the inhibition potential towards one of the most important drug-metabolizing enzymes (DMEs) UDP-glucuronosyltransferases (UGTs). in vitro incubation method using recombinant UGTs-catalyzed 4-methylumbelliferone (4-MU) glucuronidation was used to evaluate the inhibition towards important UGT isoforms in the liver, including UGT1A1, 1A3, 1A6, 1A9, and 2B7. At the same concentration (100 microM), baicalein showed stronger inhibition potential than baicalin towards all the tested UGT isoforms. Data fitting using Dixon plot and Lineweaver-Burk plot was carried out to determine the inhibition type, and the second plot with the slopes from Lineweaver-Burk plot towards baicalein's concentrations was used to calculate the inhibition kinetic parameters (K(i)). Competitive inhibition type was observed for UGT1A1, 1A6, 1A9 and 2B7, and noncompetitive inhibition was detected for UGT1A3. The inhibition kinetic parameters (K(i)) were calculated to be 1.2, 5.1, 15.3, 26.3, and 48.9 microM for UGT1A1, 1A3, 1A6, 1A9, and 2B7, respectively. All these information reminds us of the necessary monitoring when oral administration of baicalin or baicalin-containing herbs.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Flavanonas/farmacología , Flavonoides/farmacología , Glucuronosiltransferasa/antagonistas & inhibidores , Biotransformación , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacocinética , Flavanonas/farmacocinética , Flavonoides/farmacocinética , Glucurónidos/metabolismo , Himecromona/metabolismo , Indicadores y Reactivos , Isoenzimas/antagonistas & inhibidores , Cinética , Hígado/efectos de los fármacos , Hígado/enzimologíaRESUMEN
Diabetic nephropathy (DN) and diabetic retinopathy (DR) are the most serious and common diabetes-associated complications. DN and DR are all highly prevalent and dangerous global diseases, but the underlying mechanism remains to be elucidated. Ferroptosis, a relatively recently described type of cell death, has been confirmed to be involved in the occurrence and development of various diabetic complications. The disturbance of cellular iron metabolism directly triggers ferroptosis, and abnormal iron metabolism is closely related to diabetes. However, the molecular mechanism underlying the role of ferroptosis in DN and DR is still unclear, and needs further study. In this review article, we summarize and evaluate the mechanism of ferroptosis and its role and progress in DN and DR, it provides new ideas for the diagnosis and treatment of DN and DR.
Asunto(s)
Diabetes Mellitus , Nefropatías Diabéticas , Retinopatía Diabética , Ferroptosis , Enfermedades de la Retina , Humanos , Nefropatías Diabéticas/etiología , Retinopatía Diabética/etiología , HierroRESUMEN
The objective of the present study is to clearly evaluate the inhibitory effects of tacrolimus (tacro) on important UGT isoforms in human liver, including determination of inhibition kinetic type and calculation of inhibition kinetic parameters. An in vitro incubation system was used to investigate the inhibitory effect of tacro on UGT isoforms. The recombinant UGT isoforms were used as enzyme source, and a nonspecific substrate 4-methylumbelliferone (4-MU) was utilized as substrate. Among the tested UGT isoforms, UGT1A1, UGT1A3, UGT2B7 and UGT2B15 were strongly inhibited by tacro in a concentration-dependent manner. Dixon and Lineweaver-Burk plots showed that the inhibition of UGT1A1, UGT1A3, and UGT2B7 was all best fit to competitive inhibition type, and the inhibition of UGT2B15 was best fit to noncompetitive type. The inhibition kinetic parameters (Ki) were determined to be 4.7, 1.3, 1.9, and 4.3 microM for UGT1A1, UGT1A3, UGT2B7, and UGT2B15, respectively. Inhibition of these important UGT isoforms in human liver might be an important reason for clinically frequent drug-drug interaction between tacro and other drugs.
Asunto(s)
Inhibidores Enzimáticos , Glucuronosiltransferasa/antagonistas & inhibidores , Inmunosupresores/farmacología , Tacrolimus/farmacología , Biotransformación , Glucurónidos/metabolismo , Humanos , Himecromona/análogos & derivados , Himecromona/metabolismo , Indicadores y Reactivos , Isoenzimas/antagonistas & inhibidores , Cinética , Hígado/enzimología , Hígado/metabolismo , Proteínas Recombinantes/químicaRESUMEN
Mitochondrial calcium has been postulated to regulate a wide range of processes from bioenergetics to cell death. Here, we characterize a mouse model that lacks expression of the recently discovered mitochondrial calcium uniporter (MCU). Mitochondria derived from MCU(-/-) mice have no apparent capacity to rapidly uptake calcium. Whereas basal metabolism seems unaffected, the skeletal muscle of MCU(-/-) mice exhibited alterations in the phosphorylation and activity of pyruvate dehydrogenase. In addition, MCU(-/-) mice exhibited marked impairment in their ability to perform strenuous work. We further show that mitochondria from MCU(-/-) mice lacked evidence for calcium-induced permeability transition pore (PTP) opening. The lack of PTP opening does not seem to protect MCU(-/-) cells and tissues from cell death, although MCU(-/-) hearts fail to respond to the PTP inhibitor cyclosporin A. Taken together, these results clarify how acute alterations in mitochondrial matrix calcium can regulate mammalian physiology.