RESUMEN
Cardiometabolic diseases are often associated with heightened levels of angiotensin II (Ang II), which accounts for the observed oxidative stress, inflammation, and fibrosis. Accumulating evidence indicates a parallel upregulation of dipeptidyl dipeptidase 4 (DPP4) activity in cardiometabolic diseases, with its inhibition shown to mitigate oxidative stress, inflammation, and fibrosis. These findings highlight an overlap between the pathophysiological mechanisms used by Ang II and DPP4. Recent evidence demonstrates that targeted inhibition of DPP4 prevents the rise in Ang II and its associated molecules in experimental models of cardiometabolic diseases. Similarly, inhibitors of the angiotensin I-converting enzyme (ACE) or Ang II type 1 receptor (AT1R) blockers downregulate DPP4 activity, establishing a bidirectional relationship between DPP4 and Ang II. Here, we discuss the current evidence supporting the cross talk between Ang II and DPP4, along with the potential mechanisms promoting this cross regulation. A comprehensive analysis of this bidirectional relationship across tissues will advance our understanding of how DPP4 and Ang II collectively promote the development and progression of cardiometabolic diseases.
Asunto(s)
Angiotensina II , Enfermedades Cardiovasculares , Humanos , Dipeptidil Peptidasa 4 , Peptidil-Dipeptidasa A , Receptor de Angiotensina Tipo 1 , Inflamación , Fibrosis , Angiotensina IRESUMEN
BACKGROUND: Hematopoietic stem cell (HSC) therapy has shown promise for tissue regeneration after ischemia. Therefore, there is a need to understand mechanisms underlying endogenous HSCs activation in response to ischemic stress and coordination of angiogenesis and repair. SHP-1 plays important roles in HSC quiescence and differentiation by regulation of TGF-ß1 signaling. TGF-ß1 promotes angiogenesis by stimulating stem cells to secrete growth factors to initiate the formation of blood vessels and later aid in their maturation. We propose that SHP-1 responds to ischemia stress in HSC and progenitor cells (HSPC) via regulation of TGF-ß1. METHODS: A mouse hind limb ischemia model was used. Local blood perfusion in the limbs was determined using laser doppler perfusion imaging. The number of positive blood vessels per square millimeter, as well as blood vessel diameter (µm) and area (µm2), were calculated. Hematopoietic cells were analyzed using flow cytometry. The bone marrow transplantation assay was performed to measure HSC reconstitution. RESULTS: After femoral artery ligation, TGF-ß1 was initially decreased in the bone marrow by day 3 of ischemia, followed by an increase on day 7. This pattern was opposite to that in the peripheral blood, which is concordant with the response of HSC to ischemic stress. In contrast, SHP-1 deficiency in HSC is associated with irreversible activation of HSPCs in the bone marrow and increased circulating HSPCs in peripheral blood following limb ischemia. In addition, there was augmented auto-induction of TGF-ß1 and sustained inactivation of SHP-1-Smad2 signaling, which impacted TGF-ß1 expression in HSPCs in circulation. Importantly, restoration of normal T GF-ß1 oscillations helped in the recovery of limb repair and function. CONCLUSIONS: HSPC-SHP-1-mediated regulation of TGF-ß1 in both bone marrow and peripheral blood is required for a normal response to ischemic stress.
Asunto(s)
Células Madre Hematopoyéticas , Factor de Crecimiento Transformador beta1 , Ratones , Animales , Factor de Crecimiento Transformador beta1/metabolismo , Células Madre Hematopoyéticas/metabolismo , Isquemia , Extremidad InferiorRESUMEN
Recent evidence suggests that dipeptidyl peptidase-4 (DPP4) inhibition with saxagliptin (Saxa) is renoprotective under comorbid conditions associated with activation of the renin-angiotensin-aldosterone system (RAAS), such as diabetes, obesity, and hypertension, which confer a high cardiovascular risk. Immune system activation is now recognized as a contributor to RAAS-mediated tissue injury, and, importantly, immunomodulatory effects of DPP4 have been reported. Accordingly, we examined the hypothesis that DPP4 inhibition with Saxa attenuates angiotensin II (ANG II)-induced kidney injury and albuminuria via attenuation of immune activation in the kidney. To this end, male mice were infused with either vehicle or ANG II (1,000 ng/kg/min, s.c.) for 3 wk and received either placebo or Saxa (10 mg/kg/day, p.o.) during the final 2 wk. ANG II infusion increased kidney, but not plasma, DPP4 activity in vivo as well as DPP4 activity in cultured proximal tubule cells. The latter was prevented by angiotensin receptor blockade with olmesartan. Further, ANG II induced hypertension and kidney injury characterized by mesangial expansion, mitochondrial damage, reduced brush border megalin expression, and albuminuria. Saxa inhibited DPP4 activity â¼50% in vivo and attenuated ANG II-mediated kidney injury, independent of blood pressure. Further mechanistic experiments revealed mitigation by Saxa of proinflammatory and profibrotic mediators activated by ANG II in the kidney, including CD8+ T cells, resident macrophages (CD11bhiF4/80loLy6C-), and neutrophils. In addition, Saxa improved ANG II suppressed anti-inflammatory regulatory T cell and T helper 2 lymphocyte activity. Taken together, these results demonstrate, for the first time, blood pressure-independent involvement of renal DPP4 activation contributing to RAAS-dependent kidney injury and immune activation.NEW & NOTEWORTHY This work highlights the role of dipeptidyl peptidase-4 (DPP4) in promoting ANG II-mediated kidney inflammation and injury. Specifically, ANG II infusion in mice led to increases in blood pressure and kidney DPP4 activity, which then led to activation of CD8+ T cells, Ly6C- macrophages, and neutrophils and suppression of anti-inflammatory T helper 2 lymphocytes and regulatory T cells. Collectively, this led to kidney injury, characterized by mesangial expansion, mitochondrial damage, and albuminuria, which were mitigated by DPP4 inhibition independent of blood pressure reduction.
Asunto(s)
Dipeptidil Peptidasa 4/metabolismo , Hipoglucemiantes/farmacología , Macrófagos/metabolismo , Angiotensina II/farmacología , Animales , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Hipertensión/tratamiento farmacológico , Hipertensión/fisiopatología , Riñón/efectos de los fármacos , Riñón/metabolismo , Túbulos Renales Proximales/efectos de los fármacos , Túbulos Renales Proximales/metabolismo , Macrófagos/efectos de los fármacos , Masculino , RatonesRESUMEN
OBJECTIVE: Diabetic nephropathy (DN) is characterized by glomerular and tubulointerstitial injury, proteinuria and remodeling. Here we examined whether the combination of an inhibitor of neprilysin (sacubitril), a natriuretic peptide-degrading enzyme, and an angiotensin II type 1 receptor blocker (valsartan), suppresses renal injury in a pre-clinical model of early DN more effectively than valsartan monotherapy. METHODS: Sixty-four male Zucker Obese rats (ZO) at 16 weeks of age were distributed into 4 different groups: Group 1: saline control (ZOC); Group 2: sacubitril/valsartan (sac/val) (68 mg kg-1 day-1; ZOSV); and Group 3: valsartan (val) (31 mg kg-1 day-1; ZOV). Group 4 received hydralazine, an anti-hypertensive drug (30 mg kg-1 day-1, ZOH). Six Zucker Lean (ZL) rats received saline (Group 5) and served as lean controls (ZLC). Drugs were administered daily for 10 weeks by oral gavage. RESULTS: Mean arterial pressure (MAP) increased in ZOC (+ 28%), but not in ZOSV (- 4.2%), ZOV (- 3.9%) or ZOH (- 3.7%), during the 10 week-study period. ZOC were mildly hyperglycemic, hyperinsulinemic and hypercholesterolemic. ZOC exhibited proteinuria, hyperfiltration, elevated renal resistivity index (RRI), glomerular mesangial expansion and podocyte foot process flattening and effacement, reduced nephrin and podocin expression, tubulointerstitial and periarterial fibrosis, increased NOX2, NOX4 and AT1R expression, glomerular and tubular nitroso-oxidative stress, with associated increases in urinary markers of tubular injury. None of the drugs reduced fasting glucose or HbA1c. Hypercholesterolemia was reduced in ZOSV (- 43%) and ZOV (- 34%) (p < 0.05), but not in ZOH (- 13%) (ZOSV > ZOV > ZOH). Proteinuria was ameliorated in ZOSV (- 47%; p < 0.05) and ZOV (- 30%; p > 0.05), but was exacerbated in ZOH (+ 28%; p > 0.05) (ZOSV > ZOV > ZOH). Compared to ZOC, hyperfiltration was improved in ZOSV (p < 0.05 vs ZOC), but not in ZOV or ZOH. None of the drugs improved RRI. Mesangial expansion was reduced by all 3 treatments (ZOV > ZOSV > ZOH). Importantly, sac/val was more effective in improving podocyte and tubular mitochondrial ultrastructure than val or hydralazine (ZOSV > ZOV > ZOH) and this was associated with increases in nephrin and podocin gene expression in ZOSV (p < 0.05), but not ZOV or ZOH. Periarterial and tubulointerstitial fibrosis and nitroso-oxidative stress were reduced in all 3 treatment groups to a similar extent. Of the eight urinary proximal tubule cell injury markers examined, five were elevated in ZOC (p < 0.05). Clusterin and KIM-1 were reduced in ZOSV (p < 0.05), clusterin alone was reduced in ZOV and no markers were reduced in ZOH (ZOSV > ZOV > ZOH). CONCLUSIONS: Compared to val monotherapy, sac/val was more effective in reducing proteinuria, renal ultrastructure and tubular injury in a clinically relevant animal model of early DN. More importantly, these renoprotective effects were independent of improvements in blood pressure, glycemia and nitroso-oxidative stress. These novel findings warrant future clinical investigations designed to test whether sac/val may offer renoprotection in the setting of DN.
Asunto(s)
Aminobutiratos/farmacología , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Nefropatías Diabéticas/prevención & control , Glomérulos Renales/efectos de los fármacos , Túbulos Renales/efectos de los fármacos , Inhibidores de Proteasas/farmacología , Tetrazoles/farmacología , Animales , Presión Arterial/efectos de los fármacos , Biomarcadores/metabolismo , Compuestos de Bifenilo , Glucemia/metabolismo , Nefropatías Diabéticas/sangre , Nefropatías Diabéticas/patología , Nefropatías Diabéticas/fisiopatología , Modelos Animales de Enfermedad , Combinación de Medicamentos , Fibrosis , Glomérulos Renales/metabolismo , Glomérulos Renales/fisiopatología , Glomérulos Renales/ultraestructura , Túbulos Renales/metabolismo , Túbulos Renales/fisiopatología , Túbulos Renales/ultraestructura , Lípidos/sangre , Masculino , Neprilisina/antagonistas & inhibidores , Estrés Nitrosativo/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Proteinuria/fisiopatología , Proteinuria/prevención & control , Ratas Zucker , Factores de Tiempo , ValsartánRESUMEN
BACKGROUND: Arterial stiffness is emerging as an independent risk factor for the development of chronic kidney disease. The sodium glucose co-transporter 2 (SGLT2) inhibitors, which lower serum glucose by inhibiting SGLT2-mediated glucose reabsorption in renal proximal tubules, have shown promise in reducing arterial stiffness and the risk of cardiovascular and kidney disease in individuals with type 2 diabetes mellitus. Since hyperglycemia contributes to arterial stiffness, we hypothesized that the SGLT2 inhibitor empagliflozin (EMPA) would improve endothelial function, reduce aortic stiffness, and attenuate kidney disease by lowering hyperglycemia in type 2 diabetic female mice (db/db). MATERIALS/METHODS: Ten-week-old female wild-type control (C57BLKS/J) and db/db (BKS.Cg-Dock7m+/+Leprdb/J) mice were divided into three groups: lean untreated controls (CkC, n = 17), untreated db/db (DbC, n = 19) and EMPA-treated db/db mice (DbE, n = 19). EMPA was mixed with normal mouse chow at a concentration to deliver 10 mg kg-1 day-1, and fed for 5 weeks, initiated at 11 weeks of age. RESULTS: Compared to CkC, DbC showed increased glucose levels, blood pressure, aortic and endothelial cell stiffness, and impaired endothelium-dependent vasorelaxation. Furthermore, DbC exhibited impaired activation of endothelial nitric oxide synthase, increased renal resistivity and pulsatility indexes, enhanced renal expression of advanced glycation end products, and periarterial and tubulointerstitial fibrosis. EMPA promoted glycosuria and blunted these vascular and renal impairments, without affecting increases in blood pressure. In addition, expression of "reversion inducing cysteine rich protein with Kazal motifs" (RECK), an anti-fibrotic mediator, was significantly suppressed in DbC kidneys and partially restored by EMPA. Confirming the in vivo data, EMPA reversed high glucose-induced RECK suppression in human proximal tubule cells. CONCLUSIONS: Empagliflozin ameliorates kidney injury in type 2 diabetic female mice by promoting glycosuria, and possibly by reducing systemic and renal artery stiffness, and reversing RECK suppression.
Asunto(s)
Compuestos de Bencidrilo/farmacología , Glucemia/efectos de los fármacos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Angiopatías Diabéticas/prevención & control , Nefropatías Diabéticas/prevención & control , Glucósidos/farmacología , Riñón/irrigación sanguínea , Riñón/efectos de los fármacos , Circulación Renal/efectos de los fármacos , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Transportador 2 de Sodio-Glucosa/metabolismo , Rigidez Vascular/efectos de los fármacos , Albuminuria/etiología , Albuminuria/prevención & control , Animales , Glucemia/metabolismo , Línea Celular , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/genética , Angiopatías Diabéticas/etiología , Angiopatías Diabéticas/fisiopatología , Nefropatías Diabéticas/etiología , Nefropatías Diabéticas/patología , Nefropatías Diabéticas/fisiopatología , Modelos Animales de Enfermedad , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Endotelio Vascular/fisiopatología , Femenino , Proteínas Ligadas a GPI/metabolismo , Glucosuria/etiología , Glucosuria/prevención & control , Humanos , Riñón/metabolismo , Riñón/patología , Ratones Endogámicos C57BL , Ratones Mutantes , Flujo Pulsátil/efectos de los fármacos , Resistencia Vascular/efectos de los fármacos , Vasodilatación/efectos de los fármacosRESUMEN
PURPOSE OF REVIEW: To update and review novel insights into the mechanisms, measurements, and therapeutic approaches to arterial stiffness. RECENT FINDINGS: Arterial (e.g., vascular) stiffness has been shown over time to prognosticate for cardiovascular and kidney outcomes. In this context, there has been increased interest behind the mechanisms that drive arterial stiffness beyond aging and interest in how to apply newer technologies in measurement of arterial stiffness. Pulse wave velocity has been the gold standard for measurement but industry has been innovating to improve measurement with use of single-point PWV as well as pharmacologic approaches with anti-hypertensives and oral hypoglycemic agents. Emerging data on the role of the mineralocorticoid receptor, the endothelial sodium channel (EnNaC), and uric acid in arterial stiffness are promising a number of potential therapies. Newer techniques of measuring PWV for arterial stiffness and novel therapies may soon lead to better outcomes from hypertension complications.
Asunto(s)
Antihipertensivos/farmacología , Hipertensión , Rigidez Vascular , Humanos , Hipertensión/metabolismo , Hipertensión/fisiopatología , Hipertensión/terapia , Análisis de la Onda del Pulso/métodos , Terapias en Investigación , Ácido Úrico/metabolismo , Rigidez Vascular/efectos de los fármacos , Rigidez Vascular/fisiologíaRESUMEN
The protein dipeptidyl peptidase 4 (DPP4) is a target in diabetes management and reduction of associated cardiovascular risk. Inhibition of the enzymatic function and genetic deletion of DPP4 is associated with tremendous benefits to the heart, vasculature, adipose tissue, and the kidney in rodent models of obesity, diabetes and hypertension, and associated complications. The recently concluded, "Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53" trial revealed a reduction in proteinuria in chronic kidney disease patients (stages 1-3). These results have spurred immense interest in the nonenzymatic and enzymatic role of DPP4 in the kidney. DPP4 is expressed predominantly in the glomeruli and S1-S3 segments of the nephron and to a lesser extent in other segments. DPP4 is known to facilitate absorption of cleaved dipeptides and regulate the function of the sodium/hydrogen exchanger-3 in the proximal tubules. DPP4, also known as CD26, has an important role in costimulation of lymphocytes via caveolin-1 on antigen-presenting cells in peripheral blood. Herein, we present our perspectives for the ongoing interest in the role of DPP4 in the kidney.
Asunto(s)
Diabetes Mellitus/enzimología , Nefropatías Diabéticas/enzimología , Dipeptidil Peptidasa 4/metabolismo , Hipertensión/enzimología , Riñón/enzimología , Insuficiencia Renal Crónica/enzimología , Animales , Células Presentadoras de Antígenos/enzimología , Células Presentadoras de Antígenos/inmunología , Caveolina 1/metabolismo , Diabetes Mellitus/tratamiento farmacológico , Diabetes Mellitus/inmunología , Diabetes Mellitus/fisiopatología , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/inmunología , Nefropatías Diabéticas/fisiopatología , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Progresión de la Enfermedad , Humanos , Hipertensión/tratamiento farmacológico , Hipertensión/inmunología , Hipertensión/fisiopatología , Riñón/efectos de los fármacos , Riñón/inmunología , Riñón/fisiopatología , Activación de Linfocitos , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/inmunología , Insuficiencia Renal Crónica/fisiopatología , Transducción de Señal , Intercambiador 3 de Sodio-Hidrógeno , Intercambiadores de Sodio-Hidrógeno/metabolismoRESUMEN
Mammalian target for rapamycin complex 1 (mTORC1) is a common target for the action of immunosuppressant macrolide rapamycin and glucose-lowering metformin. Inhibition of mTORC1 can exert both beneficial and detrimental effects in different pathologies. Here, we investigated the differential effects of rapamycin (1.2 mg/kg per day delivered subcutaneously for 6 weeks) and metformin (300 mg/kg per day delivered orally for 11 weeks) treatments on male Zucker diabetic fatty (ZDF) rats that mimic the cardiorenal pathology of type 2 diabetic patients and progress to insulin insufficiency. Rapamycin and metformin improved proteinuria, and rapamycin also reduced urinary gamma glutamyl transferase (GGT) indicating improvement of tubular health. Metformin reduced food and water intake, and urinary sodium and potassium, whereas rapamycin increased urinary sodium. Metformin reduced plasma alkaline phosphatase, but induced transaminitis as evidenced by significant increases in plasma AST and ALT. Metformin also induced hyperinsulinemia, but did not suppress fasting plasma glucose after ZDF rats reached 17 weeks of age, and worsened lipid profile. Rapamycin also induced mild transaminitis. Additionally, both rapamycin and metformin increased plasma uric acid and creatinine, biomarkers for cardiovascular and renal disease. These observations define how rapamycin and metformin differentially modulate metabolic profiles that regulate cardiorenal pathology in conditions of severe type 2 diabetes.
Asunto(s)
Enfermedades Cardiovasculares/prevención & control , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/farmacología , Resistencia a la Insulina , Metformina/farmacología , Complejos Multiproteicos/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Sirolimus/farmacología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Animales , Biomarcadores/sangre , Biomarcadores/orina , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/enzimología , Enfermedades Cardiovasculares/etiología , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/enzimología , Nefropatías Diabéticas/enzimología , Nefropatías Diabéticas/etiología , Nefropatías Diabéticas/prevención & control , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Hígado/efectos de los fármacos , Hígado/enzimología , Masculino , Diana Mecanicista del Complejo 1 de la Rapamicina , Complejos Multiproteicos/metabolismo , Proteinuria/enzimología , Proteinuria/etiología , Proteinuria/prevención & control , Ratas Zucker , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Factores de TiempoRESUMEN
Proteinuria is a marker of incipient kidney injury in many disorders, including obesity. Previously, we demonstrated that megalin, a receptor endocytotic protein in the proximal tubule, is downregulated in obese mice, which was prevented by inhibition of dipeptidyl protease 4 (DPP4). Obesity is thought to be associated with upregulation of intra-renal angiotensin II (Ang II) signaling via the Ang II Type 1 receptor (AT1R) and Ang II suppresses megalin expression in proximal tubule cells in vitro. Therefore, we tested the hypothesis that Ang II will suppress megalin protein via activation of DPP4. We used Ang II (200 ng/kg/min) infusion in mice and Ang II (10(-8) M) treatment of T35OK-AT1R proximal tubule cells to test our hypothesis. Ang II-infused mouse kidneys displayed increases in DPP4 activity and decreases in megalin. In proximal tubule cells, Ang II stimulated DPP4 activity concurrent with suppression of megalin. MK0626, a DPP4 inhibitor, partially restored megalin expression similar to U0126, a mitogen activated protein kinase (MAPK)/extracellular regulated kinase (ERK) kinase kinase (MEK) 1/2 inhibitor and AG1478, an epidermal growth factor receptor (EGFR) inhibitor. Similarly, Ang II-induced ERK phosphorylation was suppressed with MK0626 and Ang II-induced DPP4 activity was suppressed by U0126. Therefore, our study reveals a cross talk between AT1R signaling and DPP4 activation in the regulation of megalin and underscores the significance of targeting DPP4 in the prevention of obesity related kidney injury progression.
Asunto(s)
Angiotensina II/metabolismo , Dipeptidil Peptidasa 4/metabolismo , Regulación de la Expresión Génica , Túbulos Renales Proximales/metabolismo , Proteína 2 Relacionada con Receptor de Lipoproteína de Baja Densidad/biosíntesis , Sistema de Señalización de MAP Quinasas , Angiotensina II/farmacología , Animales , Línea Celular , Inhibidores Enzimáticos/farmacología , Quinasas MAP Reguladas por Señal Extracelular/antagonistas & inhibidores , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Masculino , Ratones , Ratones Obesos , Obesidad/complicaciones , Obesidad/metabolismo , Insuficiencia Renal/etiología , Insuficiencia Renal/metabolismoRESUMEN
Overnutrition/obesity predisposes individuals, particularly women, to diastolic dysfunction (DD), an independent predictor of future cardiovascular disease. We examined whether low-dose spironolactone (Sp) prevents DD associated with consumption of a Western Diet (WD) high in fat, fructose, and sucrose. Female C57BL6J mice were fed a WD with or without Sp (1 mg·kg(-1)·day(-1)). After 4 mo on the WD, mice exhibited increased body weight and visceral fat, but similar blood pressures, compared with control diet-fed mice. Sp prevented the development of WD-induced DD, as indicated by decreased isovolumic relaxation time and an improvement in myocardial performance (Asunto(s)
Diástole/efectos de los fármacos
, Dieta Occidental
, Ventrículos Cardíacos/efectos de los fármacos
, Antagonistas de Receptores de Mineralocorticoides/administración & dosificación
, Receptores de Mineralocorticoides/efectos de los fármacos
, Espironolactona/administración & dosificación
, Disfunción Ventricular Izquierda/prevención & control
, Función Ventricular Izquierda/efectos de los fármacos
, Animales
, Cardiomegalia/patología
, Cardiomegalia/fisiopatología
, Cardiomegalia/prevención & control
, Dieta Alta en Grasa
, Sacarosa en la Dieta
, Modelos Animales de Enfermedad
, Femenino
, Fibrosis
, Fructosa
, Ventrículos Cardíacos/inmunología
, Ventrículos Cardíacos/metabolismo
, Ventrículos Cardíacos/patología
, Ventrículos Cardíacos/fisiopatología
, Mediadores de Inflamación/metabolismo
, Ratones Endogámicos C57BL
, Miocitos Cardíacos/efectos de los fármacos
, Miocitos Cardíacos/metabolismo
, Estrés Oxidativo/efectos de los fármacos
, Receptores de Mineralocorticoides/metabolismo
, Proteínas Quinasas S6 Ribosómicas 90-kDa/metabolismo
, Sarcómeros/efectos de los fármacos
, Sarcómeros/metabolismo
, Factores Sexuales
, Factores de Tiempo
, Disfunción Ventricular Izquierda/etiología
, Disfunción Ventricular Izquierda/inmunología
, Disfunción Ventricular Izquierda/metabolismo
, Disfunción Ventricular Izquierda/patología
, Disfunción Ventricular Izquierda/fisiopatología
, Presión Ventricular/efectos de los fármacos
, Remodelación Ventricular/efectos de los fármacos
RESUMEN
Incretin-based therapies are now well established for diabetes management and are among the frontline agents for control of hyperglycemia. In addition to their antihyperglycemic effects, evidence is emerging on the role of these agents on blood pressure regulation, cardioprotective and renoprotective properties. Because of the pleiotropic nature of these affects, these agents could offer significant benefits with regards to the cardiorenal metabolic complications that are part of the diabetes and obesity epidemic in the United States and worldwide. We review the various known mechanisms or pathways by which incretin based therapy exerts its regulation of blood pressure with emphasis on novel mechanisms such as inflammation/immunomodulation and oxidative stress.
Asunto(s)
Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Hipertensión/tratamiento farmacológico , Incretinas/uso terapéutico , Animales , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/inmunología , Exenatida , Péptido 1 Similar al Glucagón/agonistas , Humanos , Incretinas/inmunología , Estrés Oxidativo , Péptidos/inmunología , Péptidos/uso terapéutico , Pirazinas/inmunología , Pirazinas/uso terapéutico , Sistema Renina-Angiotensina/efectos de los fármacos , Fosfato de Sitagliptina , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Triazoles/inmunología , Triazoles/uso terapéutico , Ponzoñas/inmunología , Ponzoñas/uso terapéuticoRESUMEN
Blockade of the angiotensin (ANG) II receptor type 1 (AT(1)R) with angiotensin receptor blockers (ARBs) is widely used in the treatment of hypertension. However, ARBs are variably effective in reducing blood pressure, likely due, in part, to polymorphisms in the ARB binding pocket of the AT(1)R. Therefore, we need a better understanding of variations/polymorphisms that alter binding of ARBs in heterogeneous patient populations. The opossum proximal tubule cell (OKP) line is commonly used in research to evaluate renal sodium handling and therefore blood pressure. Investigating this issue, we found natural sequence variations in the opossum AT(1)R paralleling those observed in the human AT(1)R. Therefore, we posited that these sequence variations may explain ARB resistance. We demonstrate that OKP cells express AT(1)R mRNA, bind (125)I-labeled ANG II, and exhibit ANG II-induced phosphorylation of Jak2. However, Jak2 phosphorylation is not inhibited by five different ARBs commonly used to treat hypertension. Additionally, nonradioactive ANG II competes (125)I-ANG II efficiently, whereas a 10-fold molar excess of olmesartan and the ANG II receptor type 2 blocker PD-123319 is unable to block (125)I-ANG II binding. In contrast, ANG II binding to OKP cells stably expressing rat AT(1A)Rs, which have a conserved AT(1)R-binding pocket with human AT(1)R, is efficiently inhibited by olmesartan. A novel observation was that resistance to ARB binding to opossum AT(1)Rs correlates with variations from the human receptor at positions 108, 163, 192, and 198 within the ARB-binding pocket. These observations highlight the potential utility of evaluating AT(1)R polymorphisms within the ARB-binding pocket in various hypertensive populations.
Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Imidazoles/farmacología , Túbulos Renales Proximales/efectos de los fármacos , Zarigüeyas/genética , Receptor de Angiotensina Tipo 1/química , Receptor de Angiotensina Tipo 1/genética , Tetrazoles/farmacología , Angiotensina II/metabolismo , Angiotensina II/farmacología , Animales , Sitios de Unión , Línea Celular , Resistencia a Medicamentos/genética , Humanos , Radioisótopos de Yodo , Janus Quinasa 2/metabolismo , Túbulos Renales Proximales/citología , Filogenia , Polimorfismo Genético/genética , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , ARN Mensajero/genética , Ratas , Receptor de Angiotensina Tipo 1/metabolismo , Especificidad de la Especie , Vasoconstrictores/metabolismo , Vasoconstrictores/farmacologíaRESUMEN
The COVID-19 pandemic has changed the lives of many people around the world. Based on the available data and published reports, most people diagnosed with COVID-19 exhibit no or mild symptoms and could be discharged home for self-isolation. Considering that a substantial portion of them will progress to a severe disease requiring hospitalization and medical management, including respiratory and circulatory support in the form of supplemental oxygen therapy, mechanical ventilation, vasopressors, etc. The continuous monitoring of patient conditions at home for patients with COVID-19 will allow early determination of disease severity and medical intervention to reduce morbidity and mortality. In addition, this will allow early and safe hospital discharge and free hospital beds for patients who are in need of admission. In this review, we focus on the recent developments in next-generation wearable sensors capable of continuous monitoring of disease symptoms, particularly those associated with COVID-19. These include wearable non/minimally invasive biophysical (temperature, respiratory rate, oxygen saturation, heart rate, and heart rate variability) and biochemical (cytokines, cortisol, and electrolytes) sensors, sensor data analytics, and machine learning-enabled early detection and medical intervention techniques. Together, we aim to inspire the future development of wearable sensors integrated with data analytics, which serve as a foundation for disease diagnostics, health monitoring and predictions, and medical interventions.
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Leukemic-stem-cell-specific targeting may improve the survival of patients with acute myeloid leukemia (AML) by avoiding the ablative effects of standard regimens on normal hematopoiesis. Herein, we perform an unbiased screening of compounds targeting cell surface proteins and identify clinically used DPP4 inhibitors as strong suppressors of AML development in both murine AML models and primary human AML cells xenograft model. We find in retrovirus-induced AML mouse models that DPP4-deficient AML cell-transplanted mice exhibit delay and reversal of AML development, whereas deletion of DPP4 has no significant effect on normal hematopoiesis. DPP4 activates and sustains survival of AML stem cells that are critical for AML development in both human and animal models via binding with Src kinase and activation of nuclear factor κB (NF-κB) signaling. Thus, inhibition of DPP4 is a potential therapeutic strategy against AML development through suppression of survival and stemness of AML cells.
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Dipeptidil Peptidasa 4 , Leucemia Mieloide Aguda , Animales , Humanos , Ratones , Dipeptidil Peptidasa 4/metabolismo , Modelos Animales de Enfermedad , Leucemia Mieloide Aguda/metabolismo , Transducción de Señal , Células Madre/metabolismoRESUMEN
BACKGROUND/AIMS: The mammalian target of rapamycin (mTOR) is a serine kinase that regulates phosphorylation (p) of its target ribosomal S6 kinase (S6K1), whose activation can lead to glomerular and proximal tubular cell (PTC) injury and associated proteinuria. Increased mTOR/S6K1 signaling regulates signaling pathways that target fibrosis through adherens junctions. Recent data indicate aldosterone signaling through the mineralocorticoid receptor (MR) can activate the mTOR pathway. Further, antagonism of the MR has beneficial effects on proteinuria that occur independent of hemodynamics. METHODS: Accordingly, hypertensive transgenic TG(mRen2)27 (Ren2) rats, with elevated serum aldosterone and proteinuria, and age-matched Sprague-Dawley rats were treated with either a low dose (1 mg/kg/day) or a conventional dose (30 mg/kg/day) of spironolactone (MR antagonist) or placebo for 3 weeks. RESULTS: Ren2 rats displayed increases in urine levels of the PTC brush border lysosomal enzyme N-acetyl-ß-aminoglycosidase (ß-NAG) in conjunction with reductions in PTC megalin, the apical membrane adherens protein T-cadherin and basolateral α-(E)-catenin, and fibrosis. In concert with these abnormalities, Ren2 renal cortical tissue also displayed increased Ser2448 (p)/activation of mTOR and Thr389 (p)-S6K1 and increased 3-nitrotyrosine (3-NT) content, a marker for peroxynitrite. Low-dose spironolactone had no effect on blood pressure but decreased proteinuria and ß-NAG comparable to a conventional dose of this MR antagonist. Both doses of spironolactone attenuated ultrastructural maladaptive alterations and led to comparable reductions in (p)-mTOR/(p)-S6K1, 3-NT, fibrosis, and increased expression of α-(E)-catenin, T- and N-cadherin. CONCLUSIONS: Thereby, MR antagonism improves proximal tubule integrity by targeting mTOR/S6K1 signaling and redox status independent of changes in blood pressure.
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Túbulos Renales/efectos de los fármacos , Receptores de Mineralocorticoides/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Albuminuria/metabolismo , Albuminuria/patología , Animales , Animales Modificados Genéticamente , Presión Sanguínea , Inmunohistoquímica/métodos , Masculino , Microscopía Electrónica de Transmisión/métodos , Oxidación-Reducción , Estrés Oxidativo , Ratas , Ratas Sprague-Dawley , Proteínas Quinasas S6 Ribosómicas/metabolismo , Espironolactona/metabolismoRESUMEN
BACKGROUND/AIMS: Angiotensin (Ang) II contributes to tubulointerstitial fibrosis. Recent data highlight mammalian target of rapamycin (mTOR)/S6 kinase 1 (S6K1) signaling in tubulointerstitial fibrosis; however, the mechanisms remain unclear. Thereby, we investigated the role of Ang II on mTOR/S6K1-dependent proximal tubule (PT) injury, remodeling, and fibrosis. METHODS: We utilized young transgenic Ren2 rats (R2-T) and Sprague-Dawley rats (SD-T) treated with the Ang type 1 receptor (AT(1)R) blocker telmisartan (2 mg · kg(-1) · day(-1)) or vehicle (R2-C; SD-C) for 3 weeks to examine PT structure and function. RESULTS: Ren2 rats displayed increased systolic blood pressure, proteinuria and increased PT oxidant stress and remodeling. There were parallel increases in kidney injury molecule-1 and reductions in neprilysin and megalin with associated ultrastructural findings of decreased clathrin-coated pits, endosomes, and vacuoles. Ren2 rats displayed increased Serine(2448) phosphorylation of mTOR and downstream S6K1, in concert with ultrastructural basement membrane thickening, tubulointerstitial fibrosis and loss of the adhesion molecule N-cadherin. Telmisartan treatment attenuated proteinuria as well as the biochemical and tubulointerstitial structural abnormalities seen in the Ren2 rats. CONCLUSIONS: Our observations suggest that Ang II activation of the AT(1)R contributes to PT brush border injury and remodeling, in part, due to enhanced mTOR/S6K1 signaling which promotes tubulointerstitial fibrosis through loss of N-cadherin.
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Angiotensina II/metabolismo , Cadherinas/metabolismo , Fibrosis/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Animales , Animales Modificados Genéticamente , Adhesión Celular , Masculino , Microscopía Electrónica de Transmisión/métodos , Microvellosidades/metabolismo , Modelos Biológicos , NADPH Oxidasas/metabolismo , Estrés Oxidativo , Ratas , Ratas Sprague-Dawley , Renina/genéticaRESUMEN
The metabolic syndrome is a constellation of metabolic and vascular abnormalities that include insulin resistance with compensatory hyperinsulinemia, central or visceral obesity, hypertension, dyslipidemia, microalbuminuria, and oxidative stress as well as prothrombotic and inflammatory abnormalities that contribute to a hypercoagulable state and systemic endothelial dysfunction. Visceral adipose tissue is now known to secrete into the circulation a number of protein and nonprotein factors that regulate glucose metabolism in traditional insulin-sensitive tissue as well as nontraditional insulin-sensitive tissue including cardiovascular tissue. Collectively, this constellation of factors that lead to metabolic dysregulation contributes to a substantial risk for adverse cardiovascular and renal outcomes. The development of a particularly resistant form of hypertension in these individuals can be attributed to a number of factors including vasoconstriction from increased sympathetic activation, proinflammatory cytokines, and inappropriate activation of the renin-angiotensin-aldosterone system. The management of hypertension in such patients can be challenging and generally requires nonpharmacologic as well as pharmacologic interventions.
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Hipertensión/complicaciones , Adiponectina/metabolismo , Humanos , Hipertensión/tratamiento farmacológico , Grasa Intraabdominal/efectos de los fármacos , Grasa Intraabdominal/metabolismo , Síndrome Metabólico/tratamiento farmacológico , Síndrome Metabólico/etiología , Síndrome Metabólico/metabolismo , Obesidad/complicaciones , Obesidad/tratamiento farmacológico , Obesidad/metabolismoRESUMEN
Chronic kidney disease (CKD) is increasingly common and there is increasing recognition that early identification and management is critical in delaying progression of CKD as well as related complications. However, CKD is silent, awareness is low, and usually undetected until advanced stages. Herein, we will review screening and detection strategies for CKD as well as the importance of intervention in early stages to reduce progression and the burden of CKD.
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Técnicas de Diagnóstico Urológico , Tamizaje Masivo/métodos , Insuficiencia Renal Crónica/diagnóstico , Diagnóstico Precoz , Humanos , Insuficiencia Renal Crónica/epidemiología , Factores de RiesgoRESUMEN
Electrolytes play a pivotal role in regulating cardiovascular functions, hydration, and muscle activation. The current standards for monitoring electrolytes involve periodic sampling of blood and measurements using laboratory techniques, which are often uncomfortable/inconvenient to the subjects and add considerable expense to the management of their underlying disease conditions. The wide range of electrolytes in skin interstitial fluids (ISFs) and their correlations with those in plasma create exciting opportunities for applications such as electrolyte and circadian metabolism monitoring. However, it has been challenging to monitor these electrolytes in the skin ISFs. In this study, we report a minimally invasive microneedle-based potentiometric sensing system for multiplexed and continuous monitoring of Na+ and K+ in the skin ISFs. The potentiometric sensing system consists of a miniaturized stainless-steel hollow microneedle to prevent sensor delamination and a set of modified microneedle electrodes for multiplex monitoring. We demonstrate the measurement of Na+ and K+ in artificial ISFs with a fast response time, excellent reversibility and repeatability, adequate selectivity, and negligible potential interferences upon the addition of a physiologically relevant concentration of metabolites, dietary biomarkers, and nutrients. In addition, the sensor maintains the sensitivity after multiple insertions into the chicken skin model. Furthermore, the measurements in artificial ISFs using calibrated sensors confirm the accurate measurements of physiological electrolytes in artificial ISFs. Finally, the skin-mimicking phantom gel and chicken skin model experiments demonstrate the sensor's potential for minimally invasive monitoring of electrolytes in skin ISFs. The developed sensor platform can be adapted for a wide range of other applications, including real-time monitoring of nutrients, metabolites, and proteins.
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Técnicas Biosensibles , Líquido Extracelular , Electrólitos , Agujas , PotenciometríaRESUMEN
Renin-angiotensin system (RAS) activation contributes to kidney injury through oxidative stress. Renin is the rate-limiting step in angiotensin (ANG II) generation. Recent work suggests renin inhibition improves proteinuria comparable to ANG type 1 receptor (AT1R) blockade (ARB). Thereby, we investigated the relative impact of treatment with a renin inhibitor vs. an ARB on renal oxidative stress and associated glomerular structural and functional changes in the transgenic Ren2 rat, which manifests hypertension, albuminuria, and increased tissue RAS activity. Young Ren2 and age-matched Sprague-Dawley (SD) controls (age 6-9 wk) were treated with a renin inhibitor (aliskiren), an ARB (irbesartan), or vehicle for 21 days. Ren2 rats exhibited increases in systolic pressure (SBP), albuminuria, and renal 3-nitrotyrosine content as well as ultrastructural podocyte foot-process effacement and diminution of the podocyte-specific protein nephrin. Structural and functional alterations were accompanied by increased renal cortical ANG II, AT1R, as well as NADPH oxidase subunit (Nox2) expression compared with SD controls. Abnormalities were attenuated to a similar extent with both aliskiren and irbesartan treatment. Despite the fact the dose of irbesartan used caused a greater reduction in SBP than aliskerin treatment (P < 0.05), the effects on proteinuria, nephrin, and oxidative stress were similar between the two treatments. Our results highlight both the importance of pressor-related reductions on podocyte integrity and albuminuria as well as RAS-mediated oxidant stress largely comparable between ARB and renin inhibition treatment.