Targeted disruption of the bradykinin B2 receptor gene in mice alters the ontogeny of the renin-angiotensin system

Abstract

First published July 12, 2001; 10.1152/ajprenal.0020.2001.—Angiotensin II type 1 (AT1) receptor knockout (KO) mice exhibit an activated kallikrein-kinin system (KKS) that serves to attenuate the severity of the renal vascular phenotype in these mice (Tsuchida S, Miyazaki Y, Matsusaka T, Hunley TE, Inagami T, Fogo A, and Ichikawa I, Kidney Int 56: 509–516, 1999). Conversely, gestational high salt suppresses the fetal renin-angiotensin system (RAS) and provokes aberrant renal development in bradykinin B2-KO mice (El-Dahr SS, Harrison-Bernard LM, Dipp S, Yosipiv IV, and Meleg-Smith S, Physiol Genomics 3: 121–131, 2000). Thus the cross talk between the RAS and KKS may be critical for normal renal maturation. To further define the developmental interactions between the KKS and RAS, we examined the consequences of B2 receptor gene ablation on the expression of RAS components. Renal renin mRNA levels are 50% lower in newborn B2-KO than wild-type (WT) mice. Also, the age-related decline in renin mRNA is greater in B2-KO than WT mice (3.5- vs. 2-fold, P < 0.05). Although renal angiotensinogen (Ao) protein levels are higher in newborn B2-KO than WT mice, Ao mRNA levels are not, suggesting accumulation of Ao as a result of decreased renin-mediated cleavage. Similar age-related increases (8-fold) in angiotensin I-converting enzyme (ACE) activity are observed in B2-KO and WT mice. Renal AT1 protein levels are not different in B2-KO and WT mice. Furthermore, the developmental increases in renal kallikrein mRNA and enzymatic activity are more pronounced in B2-KO compared with WT mice (mRNA: 8- vs. 3-fold; activity: 13- vs. 6-fold, P < 0.05). We conclude that 1) bradykinin stimulates renin gene expression, 2) renal kallikrein is regulated via a negative feedback loop involving the B2 receptor, and 3) Ao, ACE, and AT1 are not bradykinin-target genes.