Expression and Role of Angiotensin II Type 2 Receptor in the Kidney and Mesangial Cells of Spontaneously Hypertensive Rats

Abstract

Angiotensin II type 2 (AT₂) receptor is developmentally regulated and exerts antiproliferative and proapoptotic actions. Genetic ablation of this receptor in mice affects regulation of blood pressure, but the involvement of the AT₂ receptor in the pathogenesis of hypertension remains unknown. In the present study, we examined developmental changes of angiotensin receptor subtypes in the kidney of stroke-prone spontaneously hypertensive rats (SHRSP), and compared them with those in normotensive Wistar-Kyoto rats (WKY). We also investigated the regulation and functional role of the AT₂ receptor in cultured mesangial cells. Receptor binding and Northern blot analyses revealed that AT₂ receptor expression is significantly lower in the SHRSP kidney than in the WKY kidney during the perinatal period, while AT₁ receptor expression is not different between them. In WKY mesangial cells, AT₂ receptor stimulation exerted a potent antiproliferative effect; this effect was not observed in SHRSP cells lacking the AT₂ receptor expression. The expression of interferon regulatory factor (IRF)-1 paralleled the growth-dependent induction of AT₂ receptor in WKY mesangial cells, and transfection of IRF-1 antisense oligonucleotide significantly suppressed AT₂ receptor expression, indicating IRF-1-dependent regulation of AT₂ receptor expression in mesangial cells. However, this induction was inefficient in SHRSP cells. Thus, we found impaired AT₂ receptor expression in the SHRSP kidney in vivo and in mesangial cells in vitro. The unbalanced expression of renal angiotensin receptor subtypes with exaggerated AT₁ receptor signaling during early life in SHRSP may play a role in the programming for hypertension and related renal injury. (Hypertens Res 2002; 25: 125-133)