Transendothelial transport of renin-angiotensin system components.
BACKGROUND
Vascular (interstitial) angiotensin (ANG) II production depends on circulating renin-angiotensin system (RAS) components. Mannose 6-phosphate (man-6-P) receptors and angiotensin II type 1 (AT(1)) receptors, via binding and internalization of (pro)renin and ANG II, respectively, could contribute to the transportation of these components across the endothelium.


OBJECTIVE
To investigate the mechanism(s) contributing to transendothelial RAS component transport.


METHODS
Human umbilical vein endothelial cells were cultured on transwell polycarbonate filters, and incubated with RAS components in the absence or presence of man-6-P, eprosartan or PD123319, to block man-6-P, AT(1) and angiotensin II type 2 (AT(2)) receptors, respectively.


RESULTS
Apically applied (pro)renin and angiotensinogen slowly entered the basolateral compartment, in a similar manner as horseradish peroxidase, a molecule of comparable size that reaches the interstitium via diffusion only. Prorenin transport was unaffected by man-6-P. Apical ANG I and ANG II rapidly reached the basolateral fluid independent of AT(1) and AT(2) receptors. Basolateral ANG II during apical ANG I application was as high as apical ANG II, whereas during apical ANG II application it was lower. During basolateral ANG I application, ANG II generation occurred basolaterally only, in an angiotensin-converting enzyme (ACE)-dependent manner.


CONCLUSIONS
Circulating (pro)renin, angiotensinogen, ANG I and ANG II enter the interstitium via diffusion, and interstitial ANG II generation is mediated, at least in part, by basolaterally located endothelial ACE.
D000803:Angiotensin I / Q000187:drug effects / Q000378:metabolism; D000804:Angiotensin II / Q000187:drug effects / Q000378:metabolism; D000808:Angiotensinogen / Q000378:metabolism / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D004792:Enzyme Precursors / Q000378:metabolism / Q000494:pharmacology; D006735:Horseradish Peroxidase / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007703:Peptidyl-Dipeptidase A / Q000187:drug effects / Q000378:metabolism; D012083:Renin / Q000187:drug effects / Q000378:metabolism / Q000494:pharmacology; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology*; D015842:Serine Proteinase Inhibitors / Q000378:metabolism / Q000494:pharmacology; D012709:Serum Albumin / Q000378:metabolism / Q000494:pharmacology; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects / Q000201:enzymology
D004792:Enzyme Precursors; D015842:Serine Proteinase Inhibitors; D012709:Serum Albumin; D000808:Angiotensinogen; D000804:Angiotensin II; D000803:Angiotensin I; D006735:Horseradish Peroxidase; D007703:Peptidyl-Dipeptidase A; D012083:Renin