Angiotensin II promotes development of the renal microcirculation through AT1 receptors.
Pharmacologic or genetic deletion of components of the renin-angiotensin system leads to postnatal kidney injury, but the roles of these components in kidney development are unknown. To test the hypothesis that angiotensin II supports angiogenesis during postnatal kidney development, we quantified CD31(+) postglomerular microvessels, performed quantitative PCR analysis of vascular growth factor expression, and measured renal blood flow by magnetic resonance. Treating rats with the angiotensin II type 1 receptor antagonist candesartan for 2 weeks after birth reduced the total length, volume, and surface area of capillaries in both the cortex and the medulla and inhibited the organization of vasa recta bundles. In addition, angiotensin II type 1 antagonism inhibited the transcription of angiogenic growth factors vascular endothelial growth factor, angiopoietin-1, angiopoietin-2, and the angiopoietin receptor Tie-2 in cortex and medulla. Similarly, Agtr1a(-/-);Agtr1b(-/-) mouse kidneys had decreased angiopoietin-1, angiopoietin-2, and Tie-2 mRNAs at postnatal day 14. To test whether increased urinary flow leads to microvascular injury, we induced postnatal polyuria with either lithium or adrenalectomy, but these did not alter vascular endothelial growth factor expression or vasa recta organization. Compared with vehicle-treated rats, renal blood flow was significantly (approximately 20%) lower in candesartan-treated rats even 14 days after candesartan withdrawal. Taken together, these data demonstrate that angiotensin II promotes postnatal expansion of postglomerular capillaries and organization of vasa recta bundles, which are necessary for development of normal renal blood flow.
Madsen
Kirsten
K
Department of Physiology and Pharmacology, University of Southern Denmark, Odense, Denmark.
Marcussen
Niels
N
Pedersen
Michael
M
Kjaersgaard
Gitte
G
Facemire
Carie
C
Coffman
Thomas M
TM
Jensen
Boye L
BL
D000315:Adrenalectomy; D042683:Angiopoietin-1 / Q000031:analogs & derivatives / Q000235:genetics; D042702:Angiopoietin-2 / Q000235:genetics; D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D002196:Capillaries / Q000254:growth & development* / Q000378:metabolism; D005260:Female; D007668:Kidney / Q000098:blood supply* / Q000254:growth & development / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D011141:Polyuria / Q000473:pathology / Q000503:physiopathology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism*; D042787:Receptor, TIE-2 / Q000235:genetics; D012079:Renal Circulation / Q000502:physiology*; D013777:Tetrazoles / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
D042683:Angiopoietin-1; D042702:Angiopoietin-2; D047228:Angiotensin II Type 1 Receptor Blockers; C467629:Angpt1 protein, rat; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D000804:Angiotensin II; D042787:Receptor, TIE-2; C081643:candesartan