Angiotensin-(1-7) in kidney disease: a review of the controversies.
Ang-(1-7) [angiotensin-(1-7)] is a biologically active heptapeptide component of the RAS (renin-angiotensin system), and is generated in the kidney at relatively high levels, via enzymatic pathways that include ACE2 (angiotensin-converting enzyme 2). The biological effects of Ang-(1-7) in the kidney are primarily mediated by interaction with the G-protein-coupled receptor Mas. However, other complex effects have been described that may involve receptor-receptor interactions with AT(1) (angiotensin II type 1) or AT(2) (angiotensin II type 2) receptors, as well as nuclear receptor binding. In the renal vasculature, Ang-(1-7) has vasodilatory properties and it opposes growth-stimulatory signalling in tubular epithelial cells. In several kidney diseases, including hypertensive and diabetic nephropathy, glomerulonephritis, tubulointerstitial fibrosis, pre-eclampsia and acute kidney injury, a growing body of evidence supports a role for endogenous or exogenous Ang-(1-7) as an antagonist of signalling mediated by AT(1) receptors and thereby as a protector against nephron injury. In certain experimental conditions, Ang-(1-7) appears to paradoxically exacerbate renal injury, suggesting that dose or route of administration, state of activation of the local RAS, cell-specific signalling or non-Mas receptor-mediated pathways may contribute to the deleterious responses. Although Ang-(1-7) has promise as a potential therapeutic agent in humans with kidney disease, further studies are required to delineate its signalling mechanisms in the kidney under physiological and pathophysiological conditions.
Kidney Research Centre, Division of Nephrology, Department of Medicine, Ottawa Hospital Research Institute, Ottawa, ON, Canada K1H 7W9.
Danielle
D
Zimmerman
Kevin D
KD
Burns
D000803:Angiotensin I / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D003928:Diabetic Nephropathies / Q000378:metabolism; D006801:Humans; D007674:Kidney Diseases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D010446:Peptide Fragments / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000502:physiology; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction
D010446:Peptide Fragments; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D044140:Receptor, Angiotensin, Type 1; D043562:Receptors, G-Protein-Coupled; D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; C000705328:Ace2 protein, mouse; C000705329:Ace2 protein, rat; D000085962:Angiotensin-Converting Enzyme 2; C118790:angiotensin I (1-7)