Potent antihypertrophic effect of the bradykinin B2 receptor system on the renal vasculature.

Tsuchida S, Miyazaki Y, Matsusaka T, Hunley TE, Inagami T, Fogo A, Ichikawa I
Kidney Int. 1999 56 (2): 509-16

PMID: 10432390 · DOI:10.1046/j.1523-1755.1999.00574.x

BACKGROUND - Angiotensin type 1 (AT1) receptor-deficient mice (Agtr1-/-), which selectively lack both AT1A and AT1B receptor genes, are characterized by 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 regulation pattern of the kinin-kallikrein system and treated with aprotinin (a kallikrein inhibitor), AcLys [D-b Nal7, Ile8] des-Arg9-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-specifically suppressed in Agtr1-/- kidneys at 2 and 3 weeks of age. Immunohistochemical staining in Agtr1-/- mice revealed tissue kallikrein staining along the nephron from connecting tubules to cortical collecting tubules in proximity to the hypertrophic vasculature, whereas tissue kallikrein staining was confined to connecting tubules in wild-type mice. Aprotinin and Hoe-140 accelerated the vascular hypertrophy significantly as determined by wall thickness ratio, whereas B1 receptor antagonism had no effect.

CONCLUSION - The kinin-kallikrein system in the Agtr1-/- mouse kidney is functionally activated by local suppression of kininase II and extensive redistribution of kallikrein to perivascular areas. This activation, specific to the kidney, serves to dampen a development of the marked vascular hypertrophy. These results demonstrate, to our knowledge for the first time, the antihypertrophic effect of the bradykinin B2 receptor system on the renal vasculature in vivo.

MeSH Terms (25)

Animals Aprotinin Arterioles Female Gene Expression Regulation, Developmental Hypertrophy Immunohistochemistry Kallikrein-Kinin System Kallikreins Kidney Male Mice Mice, Inbred C57BL Mice, Knockout Peptidyl-Dipeptidase A Receptor, Angiotensin, Type 1 Receptor, Angiotensin, Type 2 Receptor, Bradykinin B2 Receptors, Angiotensin Receptors, Bradykinin Renal Artery Renal Circulation Renin-Angiotensin System RNA, Messenger Serine Proteinase Inhibitors

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