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1.
Am J Physiol Cell Physiol ; 326(4): C1203-C1211, 2024 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-38581656

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 I
2.
Artículo en Inglés | MEDLINE | ID: mdl-38881421

RESUMEN

Sodium-glucose cotransporter 2 inhibitors (SGLT2i), initially developed for type 2 diabetes (T2D) treatment, have demonstrated significant cardiovascular and renal benefits in heart failure (HF) and chronic kidney disease (CKD), irrespective of T2D. This review provides an analysis of the multifaceted mechanisms underlying the cardiorenal benefits of SGLT2i in HF and CKD outside of the T2D context. Eight major aspects of the protective effects of SGLT2i beyond glycemic control are explored: (i) the impact on renal hemodynamics and tubuloglomerular feedback; (ii) the natriuretic effects via proximal tubule Na+/H+ exchanger NHE3 inhibition; (iii) the modulation of neurohumoral pathways with evidence of attenuated sympathetic activity; (iv) the impact on erythropoiesis, not only in the context of local hypoxia, but also systemic inflammation and iron regulation; (v) the uricosuria and mitigation of the hyperuricemic environment in cardiorenal syndromes; (vi) the multiorgan metabolic reprogramming including the potential induction of a fasting-like state, improvement in glucose and insulin tolerance and stimulation of lipolysis and ketogenesis; (vii) the vascular endothelial growth factor A (VEGF-A) upregulation and angiogenesis, and (viii) the direct cardiac effects. The intricate interplay between renal, neurohumoral, metabolic, and cardiac effects underscore the complexity of SGLT2i actions and provides valuable insights into their therapeutic implications for HF and CKD. Furthermore, this review sets the stage for future research to evaluate the individual contributions of these mechanisms in diverse clinical settings.

3.
Am J Physiol Cell Physiol ; 326(6): C1573-C1589, 2024 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-38557357

RESUMEN

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) reduce blood pressure (BP) in patients with hypertension, yet the precise molecular mechanisms remain elusive. SGLT2i inhibits proximal tubule (PT) NHE3-mediated sodium reabsorption in normotensive rodents, yet no hypotensive effect is observed under this scenario. This study examined the effect of empagliflozin (EMPA) on renal tubular sodium transport in normotensive and spontaneously hypertensive rats (SHRs). It also tested the hypothesis that EMPA-mediated PT NHE3 inhibition in normotensive rats is associated with upregulation of distal nephron apical sodium transporters. EMPA administration for 14 days reduced BP in 12-wk-old SHRs but not in age-matched Wistar rats. PT NHE3 activity was inhibited by EMPA treatment in both Wistar and SHRs. In Wistar rats, EMPA increased NCC activity, mRNA expression, protein abundance, and phosphorylation levels, but not in SHRs. SHRs showed higher NKCC2 activity and an abundance of cleaved ENaC α and γ subunits compared with Wistar rats, none of which were affected by EMPA. Another set of male Wistar rats was treated with EMPA, the NCC inhibitor hydrochlorothiazide (HCTZ), and EMPA combined with HCTZ or vehicle for 14 days. In these rats, BP reduction was observed only with combined EMPA and HCTZ treatment, not with either drug alone. These findings suggest that NCC upregulation counteracts EMPA-mediated inhibition of PT NHE3 in male normotensive rats, maintaining their baseline BP. Moreover, the reduction of NHE3 activity without further upregulation of major apical sodium transporters beyond the PT may contribute to the BP-lowering effect of SGLT2i in experimental models and patients with hypertension.NEW & NOTEWORTHY This study suggests that reduced NHE3-mediated sodium reabsorption in the renal proximal tubule may account, at least in part, for the BP-lowering effect of SGLT2 inhibitors in the setting of hypertension. It also demonstrates that chronic treatment with SGLT2 inhibitors upregulates NCC activity, phosphorylation, and expression in the distal tubule of normotensive but not hypertensive rats. SGLT2 inhibitor-mediated upregulation of NCC seems crucial to counteract proximal tubule natriuresis in subjects with normal BP.


Asunto(s)
Compuestos de Bencidrilo , Glucósidos , Hipertensión , Ratas Endogámicas SHR , Ratas Wistar , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Intercambiador 3 de Sodio-Hidrógeno , Regulación hacia Arriba , Animales , Masculino , Intercambiador 3 de Sodio-Hidrógeno/metabolismo , Intercambiador 3 de Sodio-Hidrógeno/genética , Intercambiador 3 de Sodio-Hidrógeno/antagonistas & inhibidores , Hipertensión/tratamiento farmacológico , Hipertensión/metabolismo , Hipertensión/fisiopatología , Glucósidos/farmacología , Compuestos de Bencidrilo/farmacología , Regulación hacia Arriba/efectos de los fármacos , Ratas , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Presión Sanguínea/efectos de los fármacos , Miembro 3 de la Familia de Transportadores de Soluto 12/metabolismo , Miembro 3 de la Familia de Transportadores de Soluto 12/genética , Túbulos Renales Proximales/efectos de los fármacos , Túbulos Renales Proximales/metabolismo , Riñón/metabolismo , Riñón/efectos de los fármacos
4.
Cardiovasc Diabetol ; 23(1): 221, 2024 Jun 26.
Artículo en Inglés | MEDLINE | ID: mdl-38926835

RESUMEN

BACKGROUND: The incidence of myocardial infarction (MI) and sudden cardiac death (SCD) is significantly higher in individuals with Type 2 Diabetes Mellitus (T2DM) than in the general population. Strategies for the prevention of fatal arrhythmias are often insufficient, highlighting the need for additional non-invasive diagnostic tools. The T-wave heterogeneity (TWH) index measures variations in ventricular repolarization and has emerged as a promising predictor for severe ventricular arrhythmias. Although the EMPA-REG trial reported reduced cardiovascular mortality with empagliflozin, the underlying mechanisms remain unclear. This study investigates the potential of empagliflozin in mitigating cardiac electrical instability in patients with T2DM and coronary heart disease (CHD) by examining changes in TWH. METHODS: Participants were adult outpatients with T2DM and CHD who exhibited TWH > 80 µV at baseline. They received a 25 mg daily dose of empagliflozin and were evaluated clinically including electrocardiogram (ECG) measurements at baseline and after 4 weeks. TWH was computed from leads V4, V5, and V6 using a validated technique. The primary study outcome was a significant (p < 0.05) change in TWH following empagliflozin administration. RESULTS: An initial review of 6,000 medical records pinpointed 800 patients for TWH evaluation. Of these, 412 exhibited TWH above 80 µV, with 97 completing clinical assessments and 90 meeting the criteria for high cardiovascular risk enrollment. Empagliflozin adherence exceeded 80%, resulting in notable reductions in blood pressure without affecting heart rate. Side effects were generally mild, with 13.3% experiencing Level 1 hypoglycemia, alongside infrequent urinary and genital infections. The treatment consistently reduced mean TWH from 116 to 103 µV (p = 0.01). CONCLUSIONS: The EMPATHY-HEART trial preliminarily suggests that empagliflozin decreases heterogeneity in ventricular repolarization among patients with T2DM and CHD. This reduction in TWH may provide insight into the mechanism behind the decreased cardiovascular mortality observed in previous trials, potentially offering a therapeutic pathway to mitigate the risk of severe arrhythmias in this population. TRIAL REGISTRATION: NCT: 04117763.


Asunto(s)
Compuestos de Bencidrilo , Diabetes Mellitus Tipo 2 , Glucósidos , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Compuestos de Bencidrilo/uso terapéutico , Compuestos de Bencidrilo/efectos adversos , Glucósidos/uso terapéutico , Glucósidos/efectos adversos , Masculino , Femenino , Persona de Mediana Edad , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/efectos adversos , Anciano , Diabetes Mellitus Tipo 2/mortalidad , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/fisiopatología , Resultado del Tratamiento , Factores de Tiempo , Potenciales de Acción/efectos de los fármacos , Arritmias Cardíacas/mortalidad , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/fisiopatología , Frecuencia Cardíaca/efectos de los fármacos , Enfermedad Coronaria/mortalidad , Enfermedad Coronaria/fisiopatología , Enfermedad Coronaria/tratamiento farmacológico , Enfermedad Coronaria/diagnóstico , Electrocardiografía , Factores de Riesgo
5.
Am J Physiol Renal Physiol ; 322(3): F360-F377, 2022 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-35073212

RESUMEN

The seminal studies conducted by Giebisch and coworkers in the 1960s paved the way for understanding the renal mechanisms involved in K+ homeostasis. It was demonstrated that differential handling of K+ in the distal segments of the nephron is crucial for proper K+ balance. Although aldosterone had been classically ascribed as the major ion transport regulator in the distal nephron, thereby contributing to K+ homeostasis, it became clear that aldosterone per se could not explain the ability of the kidney to modulate kaliuresis in both acute and chronic settings. The existence of alternative kaliuretic and antikaliuretic mechanisms was suggested by physiological studies in the 1980s but only gained form and shape with the advent of molecular biology. It is now established that the kidneys recruit several endocrine and paracrine mechanisms for adequate kaliuretic response. These mechanisms include the direct effects of peritubular K+, a gut-kidney regulatory axis sensing dietary K+ levels, the kidney secretion of kallikrein during postprandial periods, the upregulation of angiotensin II receptors in the distal nephron during chronic changes in K+ diet, and the local increase of prostaglandins by low-K+ diet. This review discusses recent advances in the understanding of endocrine and paracrine mechanisms underlying the modulation of K+ secretion and how these mechanisms impact kaliuresis and K+ balance. We also highlight important unknowns about the regulation of renal K+ excretion under physiological circumstances.


Asunto(s)
Aldosterona , Potasio , Aldosterona/farmacología , Homeostasis , Riñón , Nefronas , Potasio/farmacología
6.
J Am Soc Nephrol ; 32(7): 1616-1629, 2021 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-33846238

RESUMEN

BACKGROUND: SGLT2 inhibitors reduce the risk of heart failure (HF) mortality and morbidity, regardless of the presence or absence of diabetes, but the mechanisms underlying this benefit remain unclear. Experiments with nondiabetic HF rats tested the hypothesis that the SGLT2 inhibitor empagliflozin (EMPA) inhibits proximal tubule (PT) NHE3 activity and improves renal salt and water handling. METHODS: Male Wistar rats were subjected to myocardial infarction or sham operation. After 4 weeks, rats that developed HF and sham rats were treated with EMPA or untreated for an additional 4 weeks. Immunoblotting and quantitative RT-PCR evaluated SGLT2 and NHE3 expression. Stationary in vivo microperfusion measured PT NHE3 activity. RESULTS: EMPA-treated HF rats displayed lower serum B-type natriuretic peptide levels and lower right ventricle and lung weight to tibia length than untreated HF rats. Upon saline challenge, the diuretic and natriuretic responses of EMPA-treated HF rats were similar to those of sham rats and were higher than those of untreated HF rats. Additionally, EMPA treatment prevented GFR decline and renal atrophy in HF rats. PT NHE3 activity was higher in HF rats than in sham rats, whereas treatment with EMPA markedly reduced NHE3 activity. Unexpectedly, SGLT2 protein and mRNA abundance were upregulated in the PT of HF rats. CONCLUSIONS: Prevention of HF progression by EMPA is associated with reduced PT NHE3 activity, restoration of euvolemia, and preservation of renal mass. Moreover, dysregulation of PT SGLT2 may be involved in the pathophysiology of nondiabetic HF.

7.
Int J Mol Sci ; 24(1)2022 Dec 26.
Artículo en Inglés | MEDLINE | ID: mdl-36613793

RESUMEN

We examined the effects of an acute increase in blood pressure (BP) and renal sympathetic nerve activity (rSNA) induced by bicuculline (Bic) injection in the paraventricular nucleus of hypothalamus (PVN) or the effects of a selective increase in rSNA induced by renal nerve stimulation (RNS) on the renal excretion of sodium and water and its effect on sodium-hydrogen exchanger 3 (NHE3) activity. Uninephrectomized anesthetized male Wistar rats were divided into three groups: (1) Sham; (2) Bic PVN: (3) RNS + Bic injection into the PVN. BP and rSNA were recorded, and urine was collected prior and after the interventions in all groups. RNS decreased sodium (58%) and water excretion (53%) independently of BP changes (p < 0.05). However, after Bic injection in the PVN during RNS stimulation, the BP and rSNA increased by 30% and 60% (p < 0.05), respectively, diuresis (5-fold) and natriuresis (2.3-fold) were increased (p < 0.05), and NHE3 activity was significantly reduced, independently of glomerular filtration rate changes. Thus, an acute increase in the BP overcomes RNS, leading to diuresis, natriuresis, and NHE3 activity inhibition.


Asunto(s)
Riñón , Sodio , Ratas , Animales , Masculino , Sodio/metabolismo , Intercambiador 3 de Sodio-Hidrógeno , Presión Sanguínea , Ratas Wistar , Sistema Nervioso Simpático/metabolismo , Bicuculina/farmacología
8.
Am J Physiol Renal Physiol ; 320(3): F285-F296, 2021 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-33346727

RESUMEN

This study investigated the molecular mechanisms underlying the antiproteinuric effect of DPP4 inhibition in 5/6 renal ablation rats and tested the hypothesis that the urinary activity of DPP4 correlates with chronic kidney disease (CKD) progression. Experiments were conducted in male Wistar rats who underwent 5/6 nephrectomy (Nx) or sham operation followed by 8 wk of treatment with the DPP4 inhibitor (DPP4i) sitagliptin or vehicle. Proteinuria increased progressively in Nx rats throughout the observation period. This increase was remarkably mitigated by sitagliptin. Higher levels of proteinuria in Nx rats compared to control rats were accompanied by higher urinary excretion of retinol-binding protein 4, a marker of tubular proteinuria, as well as higher urinary levels of podocin, a marker of glomerular proteinuria. Retinol-binding protein 4 and podocin were not detected in the urine of Nx + DPP4i rats. Tubular and glomerular proteinuria was associated with the reduced expression of megalin and podocin in the renal cortex of Nx rats. Sitagliptin treatment partially prevented this decrease. Besides, the angiotensin II renal content was significantly reduced in the Nx rats that received sitagliptin compared to vehicle-treated Nx rats. Interestingly, both urinary DPP4 activity and abundance increased progressively in Nx rats. Additionally, urinary DPP4 activity correlated positively with serum creatinine levels, proteinuria, and blood pressure. Collectively, these results suggest that DPP4 inhibition ameliorated both tubular and glomerular proteinuria and prevented the reduction of megalin and podocin expression in CKD rats. Furthermore, these findings suggest that urinary DPP4 activity may serve as a biomarker of renal disease and progression.


Asunto(s)
Dipeptidil Peptidasa 4/orina , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Riñón/efectos de los fármacos , Proteína 2 Relacionada con Receptor de Lipoproteína de Baja Densidad/metabolismo , Proteínas de la Membrana/metabolismo , Proteinuria/prevención & control , Insuficiencia Renal Crónica/prevención & control , Fosfato de Sitagliptina/farmacología , Angiotensina II/metabolismo , Animales , Biomarcadores/orina , Modelos Animales de Enfermedad , Fibrosis , Riñón/enzimología , Riñón/patología , Masculino , Proteinuria/enzimología , Proteinuria/patología , Proteinuria/orina , Ratas Wistar , Insuficiencia Renal Crónica/enzimología , Insuficiencia Renal Crónica/patología , Insuficiencia Renal Crónica/orina , Proteínas Plasmáticas de Unión al Retinol/orina , Transducción de Señal
9.
Am J Physiol Cell Physiol ; 318(2): C328-C336, 2020 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-31721613

RESUMEN

Sodium-glucose cotransporter 2 (SGLT2) inhibitors, also known as gliflozins, improve glycemia by suppressing glucose reuptake in the renal proximal tubule. Currently, SGLT2 inhibitors are primarily indicated as antidiabetic agents; however, their benefits extend far beyond glucose control. Cardiovascular outcome trials indicated that all studied SGLT2 inhibitors remarkably and consistently reduce cardiovascular mortality and hospitalization for heart failure (HF) in type 2 diabetes (T2D) patients. Nevertheless, the mechanisms underlying the unprecedented cardiovascular benefits of gliflozins remain elusive. Multiple processes that directly or indirectly improve myocardial performance may be involved, including the amelioration of proximal tubular dysfunction. Therefore, this paper provides a perspective on the potential cellular and molecular mechanisms of the proximal tubule that may, at least in part, mediate the cardioprotection conferred by SGLT2 inhibitors. Specifically, we focus on the effects of SGLT2 on extracellular volume homeostasis, including its plausible functional and physical association with the apical Na+/H+ exchanger isoform 3 as well as its complex and its possible bidirectional interactions with the intrarenal angiotensin system and renal sympathetic nervous system. We also discuss evidence supporting a potential benefit of gliflozins in reducing cardiovascular risk, attributable to their effect on proximal tubule handling of uric acid and albumin as well as in erythropoietin production. Unraveling the mechanisms behind the beneficial actions of SGLT2 inhibitors may not only contribute to a better understanding of the pathophysiology of cardiovascular diseases but also enable repurposing of gliflozins to improve the routine management of HF patients with or without T2D.


Asunto(s)
Enfermedades Cardiovasculares/metabolismo , Sistema Cardiovascular/efectos de los fármacos , Diabetes Mellitus Tipo 2/metabolismo , Túbulos Renales Proximales/efectos de los fármacos , Riñón/metabolismo , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Transportador 2 de Sodio-Glucosa/metabolismo , Compuestos de Bencidrilo/farmacología , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Sistema Cardiovascular/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glucosa/metabolismo , Humanos , Hipoglucemiantes/farmacología , Riñón/efectos de los fármacos , Túbulos Renales Proximales/metabolismo , Sodio/metabolismo , Sistema Nervioso Simpático/efectos de los fármacos , Sistema Nervioso Simpático/metabolismo
11.
Am J Physiol Renal Physiol ; 316(5): F986-F992, 2019 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-30864843

RESUMEN

Isoform 3 of the Na+/H+ exchanger (NHE3) is responsible for the majority of the reabsorption of NaCl, NaHCO3, and, consequently, water in the renal proximal tubule. As such, this transporter plays an essential role in acid-base balance and extracellular fluid volume homeostasis and determining systemic arterial blood pressure levels. NHE3 activity is modulated by a number of mechanisms, including the redistribution of the transporter between the body of the microvilli (where NHE3 is active) and the base of the microvilli (where NHE3 is less active). Although the physiological, pathophysiological, and pharmacological importance of the subcellular distribution of NHE3 has been well established, the exact mechanism whereby NHE3 is translocated along microvilli microdomains of the proximal tubule apical membrane is unknown. Nonmuscle myosin IIA and unconventional myosin VI move cargoes in anterograde and retrograde directions, respectively, and are known to redistribute along with NHE3 in the proximal tubule in response to a variety of natriuretic and antinatriuretic stimuli, including stimulation or inhibition of the renin-angiotensin system, high dietary Na+ intake, and high blood pressure. Therefore, this review aims to discuss the current evidence that suggests a potential role of myosin IIA and myosin VI in mediating the subcellular distribution of NHE3 along the kidney proximal tubule microvilli and their possible contribution in modifying NHE3-mediated Na+ reabsorption under both physiological and pathophysiological conditions.


Asunto(s)
Túbulos Renales Proximales/metabolismo , Cadenas Pesadas de Miosina/metabolismo , Miosina Tipo IIA no Muscular/metabolismo , Reabsorción Renal , Intercambiador 3 de Sodio-Hidrógeno/metabolismo , Sodio/metabolismo , Animales , Humanos , Microvellosidades/metabolismo , Transporte de Proteínas
12.
Int J Mol Sci ; 20(8)2019 Apr 20.
Artículo en Inglés | MEDLINE | ID: mdl-31010001

RESUMEN

Dipeptidyl peptidase IV (DPPIV) inhibitors are antidiabetic agents that exert renoprotective actions independently of glucose lowering. Cardiac dysfunction is one of the main outcomes of chronic kidney disease (CKD); however, the effects of DPPIV inhibition on cardiac impairment during CKD progression remain elusive. This study investigated whether DPPIV inhibition mitigates cardiac dysfunction and remodeling in rats with a 5/6 renal ablation and evaluated if these effects are associated with changes in the cardiac renin-angiotensin system (RAS). To this end, male Wistar rats underwent a 5/6 nephrectomy (Nx) or sham operation, followed by an 8-week treatment period with the DPPIV inhibitor sitagliptin (IDPPIV) or vehicle. Nx rats had lower glomerular filtration rate, overt albuminuria and higher blood pressure compared to sham rats, whereas CKD progression was attenuated in Nx + IDPPIV rats. Additionally, Nx rats exhibited cardiac hypertrophy and fibrosis, which were associated with higher cardiac DPPIV activity and expression. The sitagliptin treatment prevented cardiac fibrosis and mitigated cardiac hypertrophy. The isovolumic relaxation time (IRVT) was higher in Nx than in sham rats, which was suggestive of CKD-associated-diastolic dysfunction. Sitagliptin significantly attenuated the increase in IRVT. Levels of angiotensin II (Ang II) in the heart tissue from Nx rats were higher while those of angiotensin-(1-7) Ang-(1-7) were lower than that in sham rats. This cardiac hormonal imbalance was completely prevented by sitagliptin. Collectively, these results suggest that DPPIV inhibition may delay the onset of cardiovascular impairment in CKD. Furthermore, these findings strengthen the hypothesis that a crosstalk between DPPIV and the renin-angiotensin system plays a role in the pathophysiology of cardiorenal syndromes.


Asunto(s)
Angiotensina II/metabolismo , Angiotensina I/metabolismo , Cardiotónicos/uso terapéutico , Miocardio/metabolismo , Fragmentos de Péptidos/metabolismo , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/metabolismo , Fosfato de Sitagliptina/uso terapéutico , Angiotensina I/sangre , Angiotensina II/sangre , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Antioxidantes/farmacología , Presión Sanguínea/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Cardiotónicos/farmacología , Diástole/efectos de los fármacos , Dipeptidil Peptidasa 4/metabolismo , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Riñón/efectos de los fármacos , Riñón/fisiopatología , Pruebas de Función Renal , Masculino , Miocardio/patología , Fragmentos de Péptidos/sangre , Peptidil-Dipeptidasa A/metabolismo , Ratas Wistar , Insuficiencia Renal Crónica/sangre , Insuficiencia Renal Crónica/fisiopatología , Sistema Renina-Angiotensina/efectos de los fármacos , Fosfato de Sitagliptina/farmacología , Regulación hacia Arriba/efectos de los fármacos , Remodelación Ventricular/efectos de los fármacos
13.
J Am Soc Nephrol ; 28(12): 3504-3517, 2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-28774999

RESUMEN

Compared with males, females have lower BP before age 60, blunted hypertensive response to angiotensin II, and a leftward shift in pressure natriuresis. This study tested the concept that this female advantage associates with a distinct sexual dimorphic pattern of transporters along the nephron. We applied quantitative immunoblotting to generate profiles of transporters, channels, claudins, and selected regulators in both sexes and assessed the physiologic consequences of the differences. In rats, females excreted a saline load more rapidly than males did. Compared with the proximal tubule of males, the proximal tubule of females had greater phosphorylation of Na+/H+ exchanger isoform 3 (NHE3), distribution of NHE3 at the base of the microvilli, and less abundant expression of Na+/Pi cotransporter 2, claudin-2, and aquaporin 1. These changes associated with less bicarbonate reabsorption and higher lithium clearance in females. The distal nephrons of females had a higher abundance of total and phosphorylated Na+/Cl- cotransporter (NCC), claudin-7, and cleaved forms of epithelial Na+ channel (ENaC) α and γ subunits, which associated with a lower baseline plasma K+ concentration. A K+-rich meal increased the urinary K+ concentration and decreased the level of renal phosphorylated NCC in females. Notably, we observed similar abundance profiles in female versus male C57BL/6 mice. These results define sexual dimorphic phenotypes along the nephron and suggest that lower proximal reabsorption in female rats expedites excretion of a saline load and enhances NCC and ENaC abundance and activation, which may facilitate K+ secretion and set plasma K+ at a lower level.


Asunto(s)
Electrólitos/metabolismo , Túbulos Renales/metabolismo , Riñón/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Caracteres Sexuales , Animales , Transporte Biológico , Presión Sanguínea , Femenino , Homeostasis , Masculino , Ratones , Ratones Endogámicos C57BL , Microvellosidades/metabolismo , Nefronas/metabolismo , Fosforilación , Potasio/metabolismo , Ratas , Ratas Sprague-Dawley , Sodio/metabolismo
14.
Am J Physiol Cell Physiol ; 311(5): C768-C776, 2016 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-27510906

RESUMEN

Binding of angiotensin II (ANG II) to the AT1 receptor (AT1R) in the proximal tubule stimulates Na+/H+ exchanger isoform 3 (NHE3) activity through multiple signaling pathways. However, the effects of ANG II/AT1R-induced inihibitory G protein (Gi) activation and subsequent decrease in cAMP accumulation on NHE3 regulation are not well established. We therefore tested the hypothesis that ANG II reduces cAMP/PKA-mediated phosphorylation of NHE3 on serine 552 and, in doing so, stimulates NHE3 activity. Under basal conditions, ANG II stimulated NHE3 activity but did not affect PKA-mediated NHE3 phosphorylation at serine 552 in opossum kidney (OKP) cells. However, in the presence of the cAMP-elevating agent forskolin (FSK), ANG II blocked FSK-induced NHE3 inhibition, reduced intracellular cAMP concentrations, lowered PKA activity, and prevented the FSK-mediated increase in NHE3 serine 552 phosphorylation. All effects of ANG II were blocked by pretreating OKP cells with the AT1R antagonist losartan, highlighting the contribution of the AT1R/Gi pathway in ANG II-mediated NHE3 upregulation under cAMP-elevating conditions. Accordingly, Gi inhibition by pertussis toxin treatment decreased NHE3 activity both in vitro and in vivo and, more importantly, prevented the stimulatory effect of ANG II on NHE3 activity in rat proximal tubules. Collectively, our results suggest that ANG II counteracts the effects of cAMP/PKA on NHE3 phosphorylation and inhibition by activating the AT1R/Gi pathway. Moreover, these findings support the notion that NHE3 dephosphorylation at serine 552 may represent a key event in the regulation of renal proximal tubule sodium handling by ANG II in the presence of natriuretic hormones that promote cAMP accumulation and transporter phosphorylation.


Asunto(s)
Angiotensina II/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , AMP Cíclico/metabolismo , Túbulos Renales Proximales/metabolismo , Fosforilación/fisiología , Intercambiadores de Sodio-Hidrógeno/metabolismo , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Animales , Línea Celular , Colforsina/metabolismo , Riñón/metabolismo , Losartán/farmacología , Masculino , Zarigüeyas , Ratas , Ratas Wistar , Receptor de Angiotensina Tipo 1/metabolismo , Transducción de Señal/fisiología , Regulación hacia Arriba/fisiología
15.
Am J Physiol Renal Physiol ; 310(2): F123-7, 2016 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-26447224

RESUMEN

Glucagon like peptide-1 (GLP-1) is an incretin hormone constantly secreted from the intestine at low basal levels in the fasted state; plasma concentrations rise rapidly after nutrient ingestion. Upon release, GLP-1 exerts insulinotropic effects via a G protein-coupled receptor, stimulation of adenylyl cyclase, and cAMP generation. Although primarily involved in glucose homeostasis, GLP-1 can induce diuresis and natriuresis when administered in pharmacological doses in humans and rodents. However, whether endogenous GLP-1 plays a role in regulating renal function remains an open question. This study aimed to test the hypothesis that blockade of GLP-1 receptor (GLP-1R) signaling at baseline influences renal salt and water handling. To this end, the GLP-1R antagonist exendin-9 (100 µg·kg(-1)·min(-1)) or vehicle was administered intravenously to overnight-fasted male Wistar rats for 30 min. This treatment reduced urinary cAMP excretion and renal cortical PKA activity, demonstrating blockade of renal GLP-1R signaling. Exendin-9-infused-rats exhibited reduced glomerular filtration rate, lithium clearance, urinary volume flow, and sodium excretion compared with vehicle-infused controls. Exendin-9 infusion also reduced renal cortical Na(+)/H(+) exchanger isotope 3 (NHE3) phosphorylation at serine 552 (NHE3pS552), a PKA consensus site that correlates with reduced transport activity. Collectively, these results provide novel evidence that GLP-1 is a physiologically relevant natriuretic factor that contributes to sodium balance, in part via tonic modulation of NHE3 activity in the proximal tubule.


Asunto(s)
Receptor del Péptido 1 Similar al Glucagón/antagonistas & inhibidores , Riñón/efectos de los fármacos , Natriuresis/efectos de los fármacos , Natriuréticos/farmacología , Fragmentos de Péptidos/farmacología , Animales , AMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Tasa de Filtración Glomerular/efectos de los fármacos , Riñón/metabolismo , Masculino , Fosforilación/efectos de los fármacos , Ratas , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Intercambiadores de Sodio-Hidrógeno/metabolismo
16.
Am J Physiol Cell Physiol ; 309(8): C541-50, 2015 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-26246427

RESUMEN

Physiological concentrations of angiotensin II (ANG II) upregulate the activity of Na(+)/H(+) exchanger isoform 3 (NHE3) in the renal proximal tubule through activation of the ANG II type I (AT1) receptor/G protein-coupled signaling. This effect is key for maintenance of extracellular fluid volume homeostasis and blood pressure. Recent findings have shown that selective activation of the beta-arrestin-biased AT1 receptor signaling pathway induces diuresis and natriuresis independent of G protein-mediated signaling. This study tested the hypothesis that activation of this AT1 receptor/beta-arrestin signaling inhibits NHE3 activity in proximal tubule. To this end, we determined the effects of the compound TRV120023, which binds to the AT1R, blocks G-protein coupling, and stimulates beta-arrestin signaling on NHE3 function in vivo and in vitro. NHE3 activity was measured in both native proximal tubules, by stationary microperfusion, and in opossum proximal tubule (OKP) cells, by Na(+)-dependent intracellular pH recovery. We found that 10(-7) M TRV120023 remarkably inhibited proximal tubule NHE3 activity both in vivo and in vitro. Additionally, stimulation of NHE3 by ANG II was completely suppressed by TRV120023 both in vivo as well as in vitro. Inhibition of NHE3 activity by TRV120023 was associated with a decrease in NHE3 surface expression in OKP cells and with a redistribution from the body to the base of the microvilli in the rat proximal tubule. These findings indicate that biased signaling of the beta-arrestin pathway through the AT1 receptor inhibits NHE3 activity in the proximal tubule at least in part due to changes in NHE3 subcellular localization.


Asunto(s)
Arrestinas/metabolismo , Túbulos Renales Proximales/citología , Receptor de Angiotensina Tipo 1/fisiología , Intercambiadores de Sodio-Hidrógeno/metabolismo , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Animales , Humanos , Concentración de Iones de Hidrógeno , Túbulos Renales Proximales/fisiología , Masculino , Oligopéptidos/farmacología , Ratas , Ratas Sprague-Dawley , Transducción de Señal , Sodio/metabolismo , Intercambiador 3 de Sodio-Hidrógeno , Intercambiadores de Sodio-Hidrógeno/genética , beta-Arrestinas
17.
Am J Physiol Regul Integr Comp Physiol ; 309(3): R215-22, 2015 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-26041113

RESUMEN

Vitamin D deficiency (VDD) is widespread in the general population. Iodinated (IC) or gadolinium-based contrast media (Gd) may decrease renal function in high-risk patients. This study tested the hypothesis that VDD is a predisposing factor for IC- or Gd-induced nephrotoxicity. To this end, male Wistar rats were fed standard (SD) or vitamin D-free diet for 30 days. IC (diatrizoate), Gd (gadoterate meglumine), or 0.9% saline was then administered intravenously and six groups were obtained as the following: SD plus 0.9% saline (Sham-SD), SD plus IC (SD+IC), SD plus Gd (SD+Gd), vitamin D-free diet for 30 days plus 0.9% saline (Sham-VDD30), vitamin D-free diet for 30 days plus IC (VDD30+IC), and vitamin D-free diet for 30 days plus Gd (VDD30+Gd). Renal hemodynamics, redox status, histological, and immunoblot analysis were evaluated 48 h after contrast media (CM) or vehicle infusion. VDD rats showed lower levels of total serum 25-hydroxyvitamin D [25(OH)D], similar plasma calcium and phosphorus concentration, and higher renal renin and angiotensinogen protein expression compared with rats fed SD. IC or Gd infusion did not affect inulin clearance-based estimated glomerular filtration rate (GFR) in rats fed SD but significantly decreased GFR in rats fed vitamin D-free diet. Both CM increased renal angiotensinogen, and the interaction between VDD and CM triggered lower renal endothelial nitric oxide synthase abundance and higher renal thiobarbituric acid reactive substances-to-glutathione ratio (an index of oxidative stress) on VDD30+IC and VDD30+Gd groups. Conversely, worsening of renal function was not accompanied by abnormalities on kidney structure. Additionally, rats on a VDD for 60 days displayed a greater fall in GFR after CM administration. Collectively, our findings suggest that VDD is a potential risk factor for IC- or Gd-induced nephrotoxicity most likely due to imbalance in intrarenal vasoactive substances and oxidative stress.


Asunto(s)
Medios de Contraste/efectos adversos , Nefropatías Diabéticas/inducido químicamente , Gadolinio/efectos adversos , Enfermedades Renales/metabolismo , Riñón/metabolismo , Deficiencia de Vitamina D/metabolismo , Animales , Modelos Animales de Enfermedad , Enfermedades Renales/fisiopatología , Masculino , Estrés Oxidativo/fisiología , Ratas Wistar , Factores de Riesgo , Vitamina D/análogos & derivados , Vitamina D/farmacología
18.
Exp Physiol ; 100(5): 502-6, 2015 Apr 20.
Artículo en Inglés | MEDLINE | ID: mdl-25858030

RESUMEN

NEW FINDINGS: What is the topic of this review? The sympathetic control of renal sodium tubular reabsorption is dependent on activation of the intrarenal renin-angiotensin system and activation of the angiotensin II type 1 (AT1 ) receptor by angiotensin II. What advances does it highlight? Despite the fact that the interaction between the sympathetic nervous system and angiotensin II regarding salt reabsorption is a well-known classical mechanism for the maintenance of extracellular volume homeostasis, the underlying molecular signalling is not clearly understood. It has been shown recently that renal nerve stimulation increases intrarenal angiotensin II and activates the AT1 receptor, triggering a signalling cascade that leads to elevations of Na(+) -H(+) exchanger isoform 3-mediated tubular transport. In this short review, the crosstalk between intrarenal angiotensin II and renal nerve activity and its effect on sodium reabsorption is addressed. In this review, we address the importance of the interaction between the sympathetic nervous system and intrarenal renin-angiotensin system in modulating renal tubular handling of sodium and water. We have recently shown that increased Na(+) -H(+) exchanger isoform 3 (NHE3) activity induced by renal nerve stimulation (RNS) depends on the activation of the angiotensin II type 1 (AT1 ) receptor by angiotensin II (Ang II). Low-frequency RNS resulted in higher levels of intrarenal angiotensinogen and Ang II independent of changes in blood pressure, the glomerular filtration rate and systemic angiotensinogen. Angiotensin II, via the AT1 receptor, triggered an intracellular pathway activating NHE3 in the renal cortex, leading to antinatriuresis and antidiuresis. Pharmacological blockade of the AT1 receptor with losartan prior to RNS abolished both the functional and the molecular responses, suggesting that intrarenal Ang II acting via the AT1 receptor is a major factor for NHE3-mediated sodium and water reabsorption induced by RNS.


Asunto(s)
Angiotensina II/metabolismo , Riñón/metabolismo , Sistema Renina-Angiotensina/fisiología , Sodio/metabolismo , Sistema Nervioso Simpático/fisiología , Animales , Tasa de Filtración Glomerular/fisiología , Humanos , Riñón/irrigación sanguínea
19.
J Am Soc Nephrol ; 25(9): 2028-39, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-24652792

RESUMEN

Na(+)-glucose cotransporter 1 (SGLT1)-mediated glucose uptake leads to activation of Na(+)-H(+) exchanger 3 (NHE3) in the intestine by a process that is not dependent on glucose metabolism. This coactivation may be important for postprandial nutrient uptake. However, it remains to be determined whether SGLT-mediated glucose uptake regulates NHE3-mediated NaHCO3 reabsorption in the renal proximal tubule. Considering that this nephron segment also expresses SGLT2 and that the kidneys and intestine show significant variations in daily glucose availability, the goal of this study was to determine the effect of SGLT-mediated glucose uptake on NHE3 activity in the renal proximal tubule. Stationary in vivo microperfusion experiments showed that luminal perfusion with 5 mM glucose stimulates NHE3-mediated bicarbonate reabsorption. This stimulatory effect was mediated by glycolytic metabolism but not through ATP production. Conversely, luminal perfusion with 40 mM glucose inhibited NHE3 because of cell swelling. Notably, pharmacologic inhibition of SGLT activity by Phlorizin produced a marked inhibition of NHE3, even in the absence of glucose. Furthermore, immunofluorescence experiments showed that NHE3 colocalizes with SGLT2 but not SGLT1 in the rat renal proximal tubule. Collectively, these findings show that glucose exerts a bimodal effect on NHE3. The physiologic metabolism of glucose stimulates NHE3 transport activity, whereas, supraphysiologic glucose concentrations inhibit this exchanger. Additionally, Phlorizin-sensitive SGLT transporters and NHE3 interact functionally in the proximal tubule.


Asunto(s)
Glucosa/metabolismo , Túbulos Renales Proximales/metabolismo , Transportador 1 de Sodio-Glucosa/metabolismo , Transportador 2 de Sodio-Glucosa/metabolismo , Intercambiadores de Sodio-Hidrógeno/metabolismo , Adenosina Trifosfato/biosíntesis , Animales , Bicarbonatos/metabolismo , Bicarbonatos/orina , Galactosa/metabolismo , Inmunohistoquímica , Túbulos Renales Proximales/efectos de los fármacos , Masculino , Metilglucósidos/metabolismo , Modelos Biológicos , Presión Osmótica , Florizina/farmacología , Ratas , Ratas Wistar , Transportador 1 de Sodio-Glucosa/antagonistas & inhibidores , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Intercambiador 3 de Sodio-Hidrógeno
20.
Int J Mol Sci ; 16(2): 4226-49, 2015 Feb 16.
Artículo en Inglés | MEDLINE | ID: mdl-25690036

RESUMEN

Dipeptidyl peptidase IV (DPPIV) is a widely expressed multifunctional serine peptidase that exists as a membrane-anchored cell surface protein or in a soluble form in the plasma and other body fluids. Numerous substrates are cleaved at the penultimate amino acid by DPPIV, including glucagon-like peptide-1 (GLP-1), brain natriuretic peptide (BNP) and stromal cell-derived factor-1 (SDF-α), all of which play important roles in the cardiovascular system. In this regard, recent reports have documented that circulating DPPIV activity correlates with poorer cardiovascular outcomes in human and experimental heart failure (HF). Moreover, emerging evidence indicates that DPPIV inhibitors exert cardioprotective and renoprotective actions in a variety of experimental models of cardiac dysfunction. On the other hand, conflicting results have been found when translating these promising findings from preclinical animal models to clinical therapy. In this review, we discuss how DPPIV might be involved in the cardio-renal axis in HF. In addition, the potential role for DPPIV inhibitors in ameliorating heart disease is revised, focusing on the effects of the main DPPIV substrates on cardiac remodeling and renal handling of salt and water.


Asunto(s)
Dipeptidil Peptidasa 4/metabolismo , Insuficiencia Cardíaca/fisiopatología , Animales , Quimiocina CXCL12/metabolismo , Dipeptidil Peptidasa 4/química , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Péptido 1 Similar al Glucagón/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/metabolismo , Humanos , Péptido Natriurético Encefálico/metabolismo
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