The causal role of dietary NaCl intake in the development of hypertension and salt sensitivity has long been recognized. The kidney sits at the fulcrum of maintaining an appropriate sodium balance and blood pressure homeostasis. As such, identifying new regulators of sodium balance in the kidney is crucial to understand the intricate mechanisms involved. Neuropeptide FF (NPFF) is a hormone expressed in the central nervous system that subserves nociception, hormonal modulation, and body temperature control. We now demonstrate for the first time that NPFF and its receptors, NPFF‐R1 and NPFF‐R2, are expressed in the kidney and endowed with pro‐hypertensive properties. The renal‐restricted bolus (1‐hr) or chronic infusion (7‐day) of NPFF increased blood pressure (*P<0.05, n=4/group) and decreased sodium excretion (UNaV; *P<0.05, N=4/group) in C57Bl/6 mice. This tubular effect was due solely to NPFF‐R2 since its silencing resulted in ~3‐fold increase in UNaV, unlike NPFF‐R1 silencing which did not affect UNaV. Therefore, we further explored the changes in NPFF‐R2 expression or activity in response to changes in salt. We now report that we have newly identified a “Sodium Response Element” (SRE), a homolog of “Dehydration‐Responsive Element” (“TACCGACAT”) in Arabidopsis thaliana genome, at the NPFF‐R2 promoter ~ 2.3 Kb upstream of the transcription start point. Exposing human renal proximal tubule cells (hRPTCs) from normal (145 μM NaCl) to low (90 μM NaCl) sodium concentration resulted in increased promoter activity (~2.5‐fold, *P<0.05, vs. DSRE, 3/group; via luciferase activity) and increased mRNA and protein expression of NPFFR2 (*P<0.05, 3–4/group; 0–8 hr). Exposure of hRPTCs from normal to high (175 μM NaCl) sodium concentration was accompanied by a reduction in promoter activity (−0.5‐fold, *P<0.05), and a decrease in mRNA and protein expression of NPFFR2 (*P<0.05, 0–8 hr). Moreover, there was a markedly increased co‐immunoprecipitation between pro‐hypertensive NPFF‐R2 and anti‐hypertensive dopamine D1 receptor, resulting in increased antagonism between the two receptors on cAMP response and sodium transport (*P<0.05, vs. fenoldopam or NPFF treatment [1 mM/30 min], 4/group). Lastly, exposure to high salt concentration resulted in greater co‐immunoprecipitation of NPFF‐R2 with Gαi3 and none with Gαs (“Gα switch”), which may explain its pro‐hypertensive activity. NPFF, via NPFF‐R2, may be a crucial determinant of sodium balance and blood pressure homeostasis and thus, may be an important target for new pharmacological and biological intervention.Support or Funding InformationR01DK039308, R01HL092196, and P01HL074940This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Introduction:The Bipolar Disorder (BD), a chronic psychiatric disorder, is highly prevalent and associated with functional disability and with excessive costs to the health system. The renin-angiotensin system (RAS) has been studied concerning neurological diseases, and the role of angiotensin II is being currently recognized as an important factor in anxiety and mood disorders. The deregulation of SRA brain is associated with the formation of reactive oxygen species, activation of pro-inflammatory pathways, reduced neuroplasticity and mitochondrial dysfunction. It is noteworthy that all these events are related to the pathophysiology of BD. Objectives: To evaluate the effect of candesartan (CDS) in an animal model of mania induced by d-amphetamine (AMPH). Methods: Adult male Swiss mice (20-25 g, n=6-8 per group) were submitted to two treatment protocols. In the prevention protocol, animals received CDS (0.1; 0.3; 1 or 3 mg/kg/day), lithium (47.5 mg/kg/day) or vehicle for 14 days and between the 8th and 14th day mice received AMPH (2 mg/kg/day ip) or saline. In the reversal protocol, AMPH or saline was administered for 14 days and between the 8th and 14th day the animals were treated with CDS, lithium or vehicle. The effect of CDS was evaluated on 14th day by examining the exploratory behavior in the open field, a test that is used for pre-clinical study of anti-manic drugs. Neurochemical tests were conducted to evaluate the oxidative stress, assessing reduced glutathione (GSH) in the prefrontal cortex (PF), hippocampus (HPC) and striatum (ST). The statistical analysis was performed by ANOVA followed by Student's-Newman-Keuls's test, considering p<0.05 as significant. Results: In both treatment protocols, there was an increase in locomotor activity in the groups that received only AMPH, which was prevented and reversed by CDS, whose results were similar to the control group and the animals that received AMPH + lithium. AMPH reduced GSH in HPC and PF in prevention and in HPC, PF and ST. GSH brain levels in CDS-treated animals increased in HPC in the prevention and in PF, HPC and ST in the reversal protocol. Conclusions: CDS, similarly to Li, is effective in reversing and preventing AMPH-induced behavioral and neurochemical alterations. The results suggest an anti-maniac action of CDS and propose a novel, safe and highly promising therapeutic approach for the BD.
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