title: Targeted disruption of the bradykinin B(2) receptor gene in mice alters the ontogeny of the renin-angiotensin system.
abstract: Angiotensin II type 1 (AT(1)) 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 B(2)-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 B(2) receptor gene ablation on the expression of RAS components. Renal renin mRNA levels are 50% lower in newborn B(2)-KO than wild-type (WT) mice. Also, the age-related decline in renin mRNA is greater in B(2)-KO than WT mice (3.5- vs. 2-fold, P < 0.05). Although renal angiotensinogen (Ao) protein levels are higher in newborn B(2)-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 B(2)-KO and WT mice. Renal AT(1) protein levels are not different in B(2)-KO and WT mice. Furthermore, the developmental increases in renal kallikrein mRNA and enzymatic activity are more pronounced in B(2)-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 B(2) receptor, and 3) Ao, ACE, and AT(1) are not bradykinin-target genes.
authors.affiliation: Section of Pediatric Nephrology, Department of Pediatrics, Tulane University Health Sciences Center, New Orleans, Louisiana 70112, USA.
authors.forename: I V
authors.initials: IV
authors.lastname: Yosipiv
authors.forename: S
authors.initials: S
authors.lastname: Dipp
authors.forename: S S
authors.initials: SS
authors.lastname: El-Dahr
mesh_terms: D000375:Aging; D000808:Angiotensinogen / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001920:Bradykinin / Q000494:pharmacology; D005246:Feedback; D015870:Gene Expression / Q000187:drug effects; D007610:Kallikreins / Q000235:genetics; D007668:Kidney / Q000254:growth & development / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D012083:Renin / Q000235:genetics; D012084:Renin-Angiotensin System / Q000235:genetics* / Q000502:physiology
chemical_list: D012333:RNA, Messenger; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin; D000808:Angiotensinogen; D007703:Peptidyl-Dipeptidase A; D007610:Kallikreins; D012083:Renin; D001920:Bradykinin