Expression and role of angiotensin II type 2 receptor in the kidney and mesangial cells of spontaneously hypertensive rats

Angiotensin II type 2 (AT(2)) 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 AT(2) 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 AT(2) receptor in cultured mesangial cells. Receptor binding and Northern blot analyses revealed that AT(2) receptor expression is significantly lower in the SHRSP kidney than in the WKY kidney during the perinatal period, while AT(1) receptor expression is not different between them. In WKY mesangial cells, AT(2) receptor stimulation exerted a potent antiproliferative effect; this effect was not observed in SHRSP cells lacking the AT(2) receptor expression. The expression of interferon regulatory factor (IRF)-1 paralleled the growth-dependent induction of AT(2) receptor in WKY mesangial cells, and transfection of IRF-1 antisense oligonucleotide significantly suppressed AT(2) receptor expression, indicating IRF-1-dependent regulation of AT(2) receptor expression in mesangial cells. However, this induction was inefficient in SHRSP cells. Thus, we found impaired AT(2) receptor expression in the SHRSP kidney in vivo and in mesangial cells in vitro. The unbalanced expression of renal angiotensin receptor subtypes with exaggerated AT(1) receptor signaling during early life in SHRSP may play a role in the programming for hypertension and related renal injury.