Potent antihypertrophic effect of the bradykinin B2 receptor system on therenal vasculature

Background. Angiotensin type 1 (AT1) receptor-deficient mice (Agtr1-/-), wh ich selectively lack both AT1A and AT1B receptor genes, are characterized b y marked intrarenal vascular thickening. In the present study, we explored the possible involvement of the kinin-kallikrein system in the development of this renal vascular hypertrophy. Methods. Wild-type and Agtr1-/- mice were examined for the developmental re gulation pattern of the kinin-kallikrein system and treated with aprotinin (a kallikrein inhibitor), AcLys [D-b Nal(7), Ile(8)] des-Arg(9)-bradykinin (a bradykinin B1 receptor antagonist), or Hoe-140 (a bradykinin B2 receptor antagonist) from 3 to 14 days of age. Results. The normal postnatal up-regulation of kininase II was organ-specif ically suppressed in Agtr1-/- kidneys at 2 nd 3 weeks of age. Immunohistoch emical staining in Agtr1-/- mice revealed tissue kallikrein staining along the nephron from connecting tubules to cortical collecting tubules in proxi mity to the hypertrophic vasculature, whereas tissue kallikrein staining wa s confined to connecting tubules in wild-type mice. Aprotinin and Hoe-140 a ccelerated the vascular hypertrophy significantly as determined by wall thi ckness ratio, whereas B1 receptor antagonism had no effect. Conclusion. The kinin-kallikrein system in the Agtr1-/- mouse kidney is fun ctionally activated by local suppression of kininase II and extensive redis tribution of kallikrein to perivascular areas. This activation, specific to the kidney, serves to dampen a development of the marked vascular hypertro phy. These results demonstrate, to our knowledge for the first time, the an tihypertrophic effect of the bradykinin B2 receptor system on the renal vas culature in vivo.