RESUMO
Accumulating evidence from clinical and experimental studies indicates that the incretin glucagon-like peptide-1 (GLP-1) elicits blood-pressure lowering effects via its diuretic, natriuretic and vasodilatory properties. The present study investigated whether acute infusion of GLP-1 induces diuresis and natriuresis in spontaneously hypertensive rats (SHRs). Additionally, we examined whether GLP-1 influences the vascular reactivity of the renal arteries of normotensive and hypertensive rats and elucidated the underlying mechanisms. We found that the increase in urinary output and urinary sodium excretion in response to systemic infusion of GLP-1 for 30min in SHRs was much less pronounced than in normotensive rats. The diuretic and natriuretic actions of GLP-1 in normotensive rats were accompanied by increases in GFR and RBF and a reduction in RVR through activation of the cAMP signaling pathway. However, no changes in renal hemodynamics were observed in SHRs. Similarly, GLP-1 induced an endothelium-independent relaxation effect in the renal arteries of normotensive rats, whereas the renal vasculature of SHRs was unresponsive to this vasodilator. The absence of a GLP-1-induced renal artery vasodilator effect in SHRs was associated with lower expression of the GLP-1 receptor, blunted GLP-1-induced increases in cAMP production and higher activity and expression of the GLP-1 inactivating enzyme dipeptidyl peptidase IV relative to the renal arteries of normotensive rats. Collectively, these results demonstrate that the renal acute responses to GLP-1 are attenuated in SHRs. Thus, chronic treatment with incretin-based agents may rely upon the upregulation of GLP-1/GLP-1 receptor signaling in the kidneys of hypertensive patients and experimental models.
Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Hipertensão/fisiopatologia , Natriurese/efeitos dos fármacos , Artéria Renal/efeitos dos fármacos , Animais , AMP Cíclico/metabolismo , Hipertensão/genética , Hipertensão/metabolismo , Hipertensão/patologia , Masculino , Ratos , Artéria Renal/metabolismo , Artéria Renal/fisiopatologia , Transdução de Sinais/efeitos dos fármacosRESUMO
Heart failure (HF) is associated with a reduced effective circulating volume that drives sodium and water retention and extracellular volume expansion. We therefore hypothesized that Na(+)/H(+) exchanger isoform 3 (NHE3), the major apical transcellular pathway for sodium reabsorption in the proximal tubule, is upregulated in an experimental model of HF. HF was induced in male rats by left ventricle radiofrequency ablation. Sham-operated rats (sham) were used as controls. At 6 wk after surgery, HF rats exhibited cardiac dysfunction with a dramatic increase in left ventricular end-diastolic pressure. By means of stationary in vivo microperfusion and pH-dependent sodium uptake, we demonstrated that NHE3 transport activity was significantly higher in the proximal tubule of HF compared with sham rats. Increased NHE3 activity was paralleled by increased renal cortical NHE3 expression at both protein and mRNA levels. In addition, the baseline PKA-dependent NHE3 phosphorylation at serine 552 was reduced in renal cortical membranes of rats with HF. Collectively, these results suggest that NHE3 is upregulated in the proximal tubule of HF rats by transcriptional, translational, and posttranslational mechanisms. Enhanced NHE3-mediated sodium reabsorption in the proximal tubule may contribute to extracellular volume expansion and edema, the hallmark feature of HF. Moreover, our study emphasizes the importance of undertaking a cardiorenal approach to contain progression of cardiac disease.