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This Article Full Text Full Text (PDF) All Versions of this Article: 296/6/F1484    most recent 90766.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Gwathmey, T. M. Articles by Chappell, M. C. PubMed PubMed Citation Articles by Gwathmey, T. M. Articles by Chappell, M. C.

Nuclear angiotensin II type 2 (AT₂) receptors are functionally linked to nitric oxide production

¹Hypertension and Vascular Research Center and ²Center for Perinatal Research, Department of Obstetrics and Gynecology, Wake Forest University School of Medicine, Winston-Salem, North Carolina

Submitted 23 December 2008 ; accepted in final form 18 February 2009

Expression of nuclear angiotensin II type 1 (AT₁) receptors in rat kidney provides further support for the concept of an intracellular renin-angiotensin system. Thus we examined the cellular distribution of renal ANG II receptors in sheep to determine the existence and functional roles of intracellular ANG receptors in higher order species. Receptor binding was performed using the nonselective ANG II antagonist ¹²⁵I-[Sar¹,Thr⁸]-ANG II (¹²⁵I-sarthran) with the AT₁ antagonist losartan (LOS) or the AT₂ antagonist PD123319 (PD) in isolated nuclei (NUC) and plasma membrane (PM) fractions obtained by differential centrifugation or density gradient separation. In both fetal and adult sheep kidney, PD competed for the majority of cortical NUC (70%) and PM (80%) sites while LOS competition predominated in medullary NUC (75%) and PM (70%). Immunodetection with an AT₂ antibody revealed a single 42-kDa band in both NUC and PM extracts, suggesting a mature molecular form of the NUC receptor. Autoradiography for receptor subtypes localized AT₂ in the tubulointerstitium, AT₁ in the medulla and vasa recta, and both AT₁ and AT₂ in glomeruli. Loading of NUC with the fluorescent nitric oxide (NO) detector DAF showed increased NO production with ANG II (1 nM), which was abolished by PD and N-nitro-L-arginine methyl ester, but not LOS. Our studies demonstrate ANG II receptor subtypes are differentially expressed in ovine kidney, while nuclear AT₂ receptors are functionally linked to NO production. These findings provide further evidence of a functional intracellular renin-angiotensin system within the kidney, which may represent a therapeutic target for the regulation of blood pressure.

nucleus; kidney; intracellular renin angiotensin system