Renal protective role of bradykinin B1 receptor in stroke-prone spontaneously hypertensive rats.
The kallikrein-kinin system plays important roles in blood pressure regulation, metabolism of electrolytes and organ protection. Although the bradykinin B2 receptor (B2R) has been reported to be involved in most of these effects, a role of the bradykinin B1 receptor (B1R) has also been noted recently. The aim of this study was to determine the role of renal B1R in stroke-prone spontaneously hypertensive rats (SHR-SP). Sixteen-week-old SHR-SP and Wistar Kyoto rats (WKY) as a control were used in the experiments. A high level of B1R mRNA was detected in SHR-SP, while the expression in WKY was almost undetectable. Immunohistochemistry revealed a B1R protein in the renal tubules and glomeruli in SHR-SP. The acute injection of a B1 R agonist into SHR-SP increased urinary NOx excretion to a level up to 5-fold higher than that in the SHR-SP treated with vehicle. The infusion of B1 R antagonist for 4 weeks resulted in a significant elevation of blood pressure and urinary albumin excretion and a decrease in urinary NOx excretion in SHR-SP. The administration of B1 R antagonist resulted in renal interstitial and glomerular fibrosis in SHR-SP. Moreover, the expressions of transforming growth factor (TGF) beta1 protein and collagen III mRNA in SHR-SP treated with B1R antagonist were significantly higher than those of SHR-SP treated with a vehicle. The expression and phosphorylation of extracellular signal-regulated protein kinase (ERK) and p38, but not c-Jun N-terminal kinase (JNK), were significantly increased in the SHR-SP treated with B1R antagonist. These results indicated that renal B1R might be over-expressed in a high blood pressure condition, and that this upregulated B1 R may play an important role in renal protection by inhibiting renal fibrosis via an increase of NO production and a suppression of TGFbeta1 expression and mitogen-activated protein kinase (ERK and p38) phosphorylation.
Hagiwara
Makoto
M
Second Department of Internal Medicine, Sapporo Medical University School of Medicine, Japan.
Murakami
Hideyuki
H
Ura
Nobuyuki
N
Agata
Jun
J
Yoshida
Hideaki
H
Higashiura
Katsuhiro
K
Shimamoto
Kazuaki
K
D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D065169:Bradykinin B1 Receptor Antagonists; D006977:Hypertension, Renal / Q000235:genetics / Q000503:physiopathology*; D016234:Kallikrein-Kinin System / Q000502:physiology; D007672:Kidney Cortex / Q000502:physiology*; D008297:Male; D017672:Nitrogen Compounds / Q000652:urine; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D043783:Receptor, Bradykinin B1 / Q000819:agonists / Q000235:genetics*; D020521:Stroke / Q000235:genetics / Q000503:physiopathology*
D065169:Bradykinin B1 Receptor Antagonists; D017672:Nitrogen Compounds; D012333:RNA, Messenger; D043783:Receptor, Bradykinin B1