RESUMEN
Chronic diabetes mellitus (DM) can lead to kidney damage associated with increased reactive oxygen species (ROS), proteinuria, and tubular damage. Altered protein expression levels of transforming growth factor-beta 1 (TGF-ß1), fibronectin, and renal NADPH oxidase (NOX-4) are associated with the profibrotic phenotype in renal tubular cells. NOX-4 is one of the primary sources of ROS in the diabetic kidney and responsible for the induction of profibrotic factors in collecting duct (CD) cells. The renal medulla is predominantly composed of CDs; in DM, these CD cells are exposed to high glucose (HG) load. Currently there is no published literature describing the expression of these markers in the renal medulla in male and female mice during the early phase of DM, or the role of NOX-4-induced ROS. Our aim was to evaluate changes in transcripts and protein abundances of TGF-ß1, fibronectin, and NOX-4 along with ROS levels in renal medullary tissues from male and female mice during a short period of streptozotocin (STZ)-induced type 1 DM and the effect of HG in cultured CD cells. CF-1 mice were injected with or without a single dose of STZ (200 mg/kg) and euthanized at day 6. STZ females showed higher expression of fibronectin and TGF-ß1 when compared to control mice of either gender. Interestingly, STZ female mice showed a >30-fold increase on mRNA levels and a 3-fold increase in protein levels of kidney medullary NOX-4. Both male and female STZ mice showed increased intrarenal ROS. In primary cultures of inner medullary CD cells exposed to HG over 48 h, the expression of TGF-ß1, fibronectin, and NOX-4 were augmented. M-1 CD cells exposed to HG showed increased ROS, fibronectin, and TGF-ß1; this effect was prevented by NOX-4 inhibition. Our data suggest that at as early as 6 days of STZ-induced DM, the expression of profibrotic markers TGF-ß1 and fibronectin increases in renal medullary CD cells. Antioxidants mechanisms in male and female in renal medullary tissues seems to be differentially regulated by the actions of NOX-4.
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Diabetes mellitus (DM) causes high glucose (HG) levels in the plasma and urine. The (pro)renin receptor (PRR) is a key regulator of renal Na+ handling. PRR is expressed in intercalated (IC) cells of the collecting duct (CD) and binds renin to promote angiotensin (Ang) II formation, thereby contributing to Na+ reabsorption. In DM, the Kreb's cycle is in a state of suppression in most tissues. However, in the CD, expression of glucose transporters is augmented, boosting the Kreb's cycle and consequently causing α-ketoglutarate (αKG) accumulation. The αKG receptor 1 (OXGR1) is a Gq-coupled receptor expressed on the apical membrane of IC cells of the CD. We hypothesize that HG causes αKG secretion and activation of OXGR1, which increases PRR expression in CD cells. This effect then promotes intratubular AngII formation and Na+ reabsorption. To test this hypothesis, streptozotocin (STZ)-induced diabetic mice were treated with or without montelukast (ML), an OXGR1 antagonist, for 6 days. STZ mice had higher urinary αKG and PRR expression along with augmented urinary AngII levels and Na+ retention. Treatment with ML prevented all these effects. Similarly, primary cultured inner medullary CD cells treated with HG showed increased PRR expression, while OXGR1 antagonist prevented this effect. αKG increases PRR expression, while treatments with ML, PKC inhibition, or intracellular Ca2+ depletion impair this effect. In silico analysis suggested that αKG binds to mouse OXGR1. These results indicate that HG conditions promote increased levels of intratubular αKG and OXGR1-dependent PRR upregulation, which impact AngII formation and Na+ reabsorption.
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Obesity has been firmly established as a major risk factor for common disease states including hypertension, type 2 diabetes mellitus, and chronic kidney disease. Increased body mass index (BMI) contributes to the activation of both the systemic and intra-tubular renin angiotensin systems (RAS), which are in turn associated with increased blood pressure (BP) and kidney damage. In this cross-sectional study, 43 subjects of normal or increased body weight were examined in order to determine the correlation of BMI or body fat mass (BFM) with blood pressure, fasting blood glucose (FBG), and urinary kidney injury markers such as interleukin-18 (IL-18), connective tissue growth factor (CTGF), neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1 (KIM-1). Our results showed that: (1) subjects with increased body weight showed significantly higher BP, BFM, total body water and metabolic age; (2) BMI was positively correlated to both systolic (R2 = 0.1384, P = 0.01) and diastolic BP (R2 = 0.2437, P = 0.0008); (3) BFM was positively correlated to DBP (R2 = 0.1232, P = 0.02) and partially correlated to urine protein (R2 = 0.047, P = 0.12) and FBG (R2 = 0.07, P = 0.06); (4) overweight young adults had higher urinary mRNA levels of renin, angiotensinogen, IL-18 and CTGF. These suggest that BMI directly affects BP, kidney injury markers, and the activation of the intra-tubular RAS even in normotensive young adults. Given that BMI measurements and urine analyses are non-invasive, our findings may pave the way to developing a new and simple method of screening for the risk of chronic kidney disease in adults.
Asunto(s)
Biomarcadores/orina , Riñón/lesiones , Riñón/metabolismo , Sobrepeso/genética , Sobrepeso/orina , Sistema Renina-Angiotensina/genética , Tejido Adiposo , Adiposidad , Adolescente , Angiotensinógeno/metabolismo , Glucemia/metabolismo , Presión Sanguínea , Índice de Masa Corporal , Factor de Crecimiento del Tejido Conjuntivo/genética , Factor de Crecimiento del Tejido Conjuntivo/orina , Ayuno/sangre , Femenino , Humanos , Interleucina-18/genética , Interleucina-18/orina , Riñón/fisiopatología , Modelos Lineales , Masculino , ARN Mensajero/genética , ARN Mensajero/metabolismo , Renina/metabolismo , Adulto JovenRESUMEN
The cytotoxic mechanism of the saponin QS-21 and its aglycone quillaic acid (QA) was studied on human gastric cancer cells (SNU1 and KATO III). Both compounds showed in vitro cytotoxic activity with IC50 values: 7.1 µM (QS-21) and 13.6 µM (QA) on SNU1 cells; 7.4 µM (QS-21) and 67 µM (QA) on KATO III cells. QS-21 and QA induce apoptosis on SNU1 and KATO III, as demonstrated by TUNEL, Annexin-V and Caspase Assays. Additionally, we performed in silico docking studies simulating the binding of both triterpenic compounds to key proteins involved in apoptotic pathways. The binding energies (∆Gbin) thus calculated, suggest that the pro-apoptotic protein Bid might be a plausible target involved in the apoptotic effect of both triterpenic compounds. Although QA shows some antiproliferative effects on SNU1 cells cultured in vitro, our results suggest that QS-21 is a more powerful antitumor agent, which merits further investigation regarding their properties as potential therapeutic agents for gastric cancer.
Asunto(s)
Antineoplásicos/química , Apoptosis/efectos de los fármacos , Ácido Oleanólico/análogos & derivados , Quillaja , Saponinas/química , Neoplasias Gástricas/tratamiento farmacológico , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Humanos , Simulación del Acoplamiento Molecular , Ácido Oleanólico/química , Ácido Oleanólico/farmacología , Ácido Oleanólico/uso terapéutico , Saponinas/farmacología , Saponinas/uso terapéuticoRESUMEN
Different pathways activated by morphogens of the early embryonic development, such as the Wnt and the Bone Morphogenetic Protein (BMP) ligands, are involved in diverse physiological and pathological conditions of the nervous system, including neurodegeneration. In this work, we have analyzed the endogenous activity of the canonical Wnt/ß-catenin and BMP/Smad-dependent pathways in an in vitro model of amyotrophic lateral sclerosis (ALS), given by motor neuron-like NSC34 cells stably expressing wild-type or G93A mutated forms of human Cu/Zn superoxide dismutase-1 (SOD1). As ALS-derived motor neurons, NSC34 cells expressing mutated hSOD1 show a decreased proliferation rate, are more susceptible to oxidation-induced cell death and display Golgi fragmentation. In addition, they display an impaired ability to induce the expression of the motor neuronal marker Hb9 and, consistently, to morphologically differentiate into a motor neuronal phenotype. Regarding signaling, our data show that the transcriptional activity associated to the Wnt/ß-catenin pathway is decreased, a finding possibly associated to the cytosolic aggregation of ß-catenin. In turn, the BMP-dependent phosphorylation of Smad1 and the transcriptional activation of the BMP/Smad pathway is increased in the pathologic model. Together, these findings suggest that Wnt/ß-catenin and the BMP-dependent pathways could play relevant roles in the neurodegeneration of motor neurons in the context of ALS.
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El boletín informativo 2 interactuemos y su equipo buscan orientar el que hacer de las EAPB para el cumplimiento del actual Plan Decenal de Salud Pública 2.012-2.021 que define en sus lineamientos la orientación a fortalecer el desarrollo de la Salud Pública con la toma de decisiones oportunas y mejoramiento de capacidades de acción. Por esta razón en Bogotá se ha considerado de importancia el generar espacios de interacción con las EAPB para llevar a cabo la asistencia técnica y la asesoría. Dentro del documento se mencionan los avances en el trabajo realizado con las aseguradoras, la asistencia de las AEPB en las mesas de trabajo de las aseguradoras, los resultados de la evaluación de los Plan Operativo Anual 2014 presentados por la EAPB, los desafíos para la asistencia técnica y se finaliza con las conclusiones y recomendaciones.
Asunto(s)
Humanos , Orientación , Salud Pública , Desarrollo de la Salud , Toma de Decisiones , AseguradorasRESUMEN
El boletín informativo 2 interactuemos brindan la oportunidad de expandir el conocimiento sobre las políticas, programas y acciones que pretenden mejorar la salud de la población; plantear cambios y proponer retos en los nuevos tiempos para ser desarrollados conjuntamente, como garantes de la salud de la población de la ciudad. En el primer número del boletín se presenta el trabajo desarrollado por la SDS y las EAPB, en el proceso de construcción de los planes indicativos 2013 2016 y los planes operativos anuales 2013, dando lugar a lecciones aprendidas, que permiten identificar debilidades y fortalezas, pero también oportunidades de mejora al momento de armonizarlos con el Plan Decenal de Salud Publica 2012 -2021.