Angiotensin II Promotes Development of the Renal Microcirculation through AT1 Receptors

Abstract

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 ϩ 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 Ϫ/Ϫ ;Agtr1b Ϫ/Ϫ 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.

Development of the Renal Arterioles

“…The growth effects of angiotensin II are not limited to the renal arterioles and extend to the postglomerular circulation. Recent work from Madsen et al 50 indicate that treatment with candesartan for 2 weeks reduces the length, volume, and surface area of capillaries in both the cortex and the medulla and inhibits the proper organization of vasa recta bundles. These findings are accompanied by inhibition of VEGF, angiopoietin-1 and -2, and the angiopoietin receptor Tie-2.…”

Tubular Vascular Endothelial Growth Factor-A, Erythropoietin, and Medullary Vessels

“…14 The developmental VEGF tub phenotype in the renal medulla is remarkably similar to that induced by an angiotensin II type 1 antagonist in neonatal rats, which downregulates VEGF-A, angiopoietin-1, angiopoietin-2, and the tie-2 receptor, suggesting that angiotensin II/AT1 A signaling promotes expansion of postglomerular capillary through several angiogenic factors. 15 Proliferation of SMA1 cells along with renal EPO producing cells in the interstitium of VEGF tub occurred only after an approximately 20% drop in hematocrit, suggesting that this fibrosis-like response is EPO independent (EPO mRNA change is similar to C57 controls), and may involve increased PDGF receptor (PDGFR) signaling, known to be induced by acute hypoxia and to cause myofibroblast proliferation (SMA1/PDGFRb1 cells). 16 Further studies are needed to evaluate whether this process is reversible or leads to fibrosis and CKD, as reported in unilateral ureteral obstruction.…”

Development of the kidney medulla

“…39,40 Treatment of newborn rats with the specific AT1R antagonist reduces length, volume and surface area of capillaries in the renal medulla, and inhibits cell proliferation and organization of the developing vasa recta bundles. 41 These changes are accompanied by decreased expression of angiogenic growth factors such as vascular endothelial growth factor (VEGF), angiopoietins 1 and 2, Flk1/Flt1 and Tie1 in the medulla, and lead to decreased renal blood flow later in life. Moreover, administration of AT1R antagonist during pregnancy in humans results in atrophy of the renal medulla and poorly developed vasa recta in the fetal kidney.…”

“…48 In addition, VEGF mRNA is detected in the outer medullary collecting ducts dissected from the developing rat kidney on P14. 41 Moreover, the expression of HIF-1, HIF-2 and VEGF, a crucial regulator of vascular development, is induced in embryonic kidneys maintained in hypoxic organ cultures. 48 These data suggest that HIF stabilization by hypoxia may be critical for VEGF production and kidney vascular development.…”