Hypothalamic SOCS-3 expression and the effect of intracerebroventricular angiotensin II injection on water intake and renal sodium handling in SHR.
In rats, the acute central dipsogenic and natriuretic action of angiotensin II (AngII) seems to be independent of the hemodynamic effects of the peptide; however, in genetically hypertensive models, this relationship has not yet been investigated. It has been demonstrated that AngII induces the suppressor of cytokine signaling (SOCS-3) expression in the brain that, in turn, modulates further activation of the pathway, leading to desensitization to AngII stimuli with regard to its dipsogenic effect. This study investigates age-related Janus kinase (JAK-2) and SOCS-3 hypothalamic expression, by immunoblotting, and the involvement of SOCS-3 expression in urinary sodium handling and dipsogenic response in spontaneously hypertensive rats (SHR), compared with age-matched Wistar-Kyoto (WKy) rats. The intracerebroventricular (i.c.v.) application of AngII significantly enhanced the dipsogenic response, reduced C(Cr), and reciprocally promoted increased absolute and fractional rates of excretion of sodium in WKy rats. The central AngII-induced dipsogenic effect in WKy and SHR was significantly attenuated by prior i.c.v. administration of DUP753. In addition, the magnitude of the dipsogenic and renal response to AngII was significantly attenuated in age-matched SHR. Blocking of hypothalamic SOCS-3 expression by an antisense oligonucleotide resulted in partial reversal of the refractory nature of AngII in thirst responses in SHR. The altered centrally applied AngII response in SHR associated with increased hypothalamic JAK-2/SOCS-3 expression may suggest that abnormal regulation of the central angiotensin pathways may contribute to dysfunction of water-electrolyte homeostasis in SHR.
Zapparoli
Adriana
A
Disciplina de Medicina Interna, Laboratório de Metabolismo Hidro-Salino, Núcleo de Medicina e Cirurgia Experimental, Departamento de Clínica Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, 13083-592 Campinas, SP, Brazil.
Calegari
Vivian
V
Velloso
Lício Augusto
LA
Guadagnini
Dioze
D
Boer
Patrícia Aline
PA
Gontijo
José Antonio Rocha
JA
D000804:Angiotensin II / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D004326:Drinking / Q000187:drug effects*; D007031:Hypothalamus / Q000378:metabolism*; D007276:Injections, Intraventricular; D053614:Janus Kinase 2 / Q000096:biosynthesis; D007668:Kidney / Q000502:physiology; D019808:Losartan / Q000494:pharmacology; D008297:Male; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D012964:Sodium / Q000652:urine*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000096:biosynthesis*
D016376:Oligonucleotides, Antisense; C491410:Socs3 protein, rat; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D000804:Angiotensin II; D012964:Sodium; C507927:Jak2 protein, rat; D053614:Janus Kinase 2; D019808:Losartan