Expression and role of angiotensin II type 2 receptor in the kidney and mesangial cells of spontaneously hypertensive rats.
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.
Goto
Masahisa
M
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Japan.
Mukoyama
Masashi
M
Sugawara
Akira
A
Suganami
Takayoshi
T
Kasahara
Masato
M
Yahata
Kensei
K
Makino
Hisashi
H
Suga
Shinichi
S
Tanaka
Issei
I
Nakao
Kazuwa
K
D000375:Aging / Q000378:metabolism; D000818:Animals; D015152:Blotting, Northern; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D004622:Embryo, Mammalian / Q000378:metabolism; D005314:Embryonic and Fetal Development; D020022:Genetic Predisposition to Disease; D005920:Glomerular Mesangium / Q000196:embryology / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D006973:Hypertension / Q000378:metabolism* / Q000473:pathology; D050856:Interferon Regulatory Factor-1; D007668:Kidney / Q000196:embryology / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D010750:Phosphoproteins / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats / Q000196:embryology; D011918:Rats, Inbred SHR / Q000235:genetics / Q000502:physiology*; D011921:Rats, Inbred WKY; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000235:genetics / Q000378:metabolism*; D020521:Stroke / Q000235:genetics
D004268:DNA-Binding Proteins; D050856:Interferon Regulatory Factor-1; C494259:Irf1 protein, rat; D010750:Phosphoproteins; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin