CARLA PATRICIA AMORIM CARNEIRO DE MORAIS
Projetos de Pesquisa
Unidades Organizacionais
LIM/13 - Laboratório de Genética e Cardiologia Molecular, Hospital das Clínicas, Faculdade de Medicina
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conferenceObject Activation of the AT1 receptor-beta-arrestin signaling pathway inhibits NHE3 activity in the renal proximal tubule(2014) MORAIS, Carla Carneiro de; OLIVEIRA-SOUZA, Maria; PESSOA, Thaissa; MALNIC, Gerhard; KRIEGER, Jose; GIRARDI, Adriana- Proximal tubule NHE3 activity is inhibited by beta-arrestin-biased angiotensin II type 1 receptor signaling(2015) MORAIS, Carla P. Carneiro de; POLIDORO, Juliano Z.; RALPH, Donna L.; PESSOA, Thaissa D.; OLIVEIRA-SOUZA, Maria; BARAUNA, Valerio G.; REBOUCAS, Nancy A.; MALNIC, Gerhard; MCDONOUGH, Alicia A.; GIRARDI, Adriana C. C.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.
- Angiotensin II counteracts the effects of cAMP/PKA on NHE3 activity and phosphorylation in proximal tubule cells(2016) CRAJOINAS, Renato O.; POLIDORO, Juliano Z.; MORAIS, Carla P. A. Carneiro de; CASTELO-BRANCO, Regiane C.; GIRARDI, Adriana C. C.Binding of angiotensin II (ANG II) to the AT(1) receptor (AT(1)R) in the proximal tubule stimulates Na+/H+ exchanger isoform 3 (NHE3) activity through multiple signaling pathways. However, the effects of ANG II/AT(1)R-induced inihibitory G protein (G(1)) 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 AT(1)R antagonist losartan, highlighting the contribution of the AT(1)R/G(i) pathway in ANG II-mediated NHE3 upregulation under cAMP-elevating conditions. Accordingly, G(i) 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 AT(1)R/G(i) 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.
bookPart 0 Citação(ões) na Scopus The aquaretic effect of vasopressin V2 receptor antagonists(2013) GIRARDI, A. C. C.; CARRARO-LACROIX, L. R.; MORAIS, C. A. C. DeThe control of body osmolality is crucial for the maintenance of normal cell volume and can be accomplished by controlling water balance. The kidneys represent the major route for the elimination of water from the body, and water balance can be achieved without affecting the renal excretion of other electrolytes. In the kidney, the hormone arginine vasopressin (AVP) remarkably increases the permeability of the distal nephron to water by increasing the density of the water channel aquaporin 2 (AQP2). More specifically, AVP binds to its V2 receptor located at the basolateral membrane of the collecting duct cells, activates the cAMP/PKA signal transduction pathway and induces translocation of the AQP2 from cytoplasmic storage vesicles to the apical membrane. The development of bioavailable AVP antagonists with a high affinity for V2 receptors represents a promising approach for the treatment of hypervolemic and euvolemic hyponatremia due to its unique aquaretic effect. The goals of this chapter are to describe the physiology of vasopressin and the role of this hormone in water balance and to discuss the pharmacodynamics and pharmacokinetics of VAPTANS (nonpeptide vasopressin receptor antagonists), as well as their current and predictable therapeutic uses, based on recent data from pre-clinical studies and clinical trials. © 2013 Nova Science Publishers, Inc.