id: PW:0000492 rgd_url: https://rgd.mcw.edu/rgdweb/pathway/pathwayRecord.html?processType=view&species=Rat&acc_id=PW:0000492 title: renin-angiotensin cascade pathway description_xrefs: - KEGG:map04614 description: Renin-angiotensin system (RAS) signaling pathway is well known for its cardiovascular roles primarily via the circulating or 'classical' route and also, has become recognized as a complex system with pleiotropic effects that engages both the circulating and the local or 'tissue' routes. Originally viewed as solely endocrine, the system is now regarded as an endocrine, paracrine and autocrine one producing an array of diverse and many times opposing actions. Underlying the system's ability of producing so many outcomes is the generation of several active peptides that signal through distinct receptors. The inactive angiotensinogen precursor Agt is the sole substrate of renin aspartyl protease whose inactive proenzyme form is prorenin. Prorenin can bind the renin receptor and display catalytic activity, presumably the consequence of an induced conformational change prompting a transition from the close-inactive to the open-active state. Receptor-bound renin has a higher catalytic activity than renin in solution. The receptor triggers several intracellular signaling pathways in a renin-dependent as well as independent fashion, the latter being promoted by a processed, truncated receptor (several MAPKs pathways are renin-dependent whereas Wnt pathways are renin-independent). A second non-specific receptor known as the mannose-6-phosphate receptor acts mostly as a clearance receptor. Binding of Renbp to renin inhibits its catalytic activity. The product of renin is the inactive peptide AgtI, in turn the substrate of Ace. Cleavage of AgtI by Ace results in the potent AgtII peptide. AgtII elicits two distinct signaling pathways via receptors type 1 and 2, Agtr1 and Agtr2, respectively. Agtr1 mediated pathway is involved in vasoconstriction, proliferation and fluid homeostasis. Its powerful but potentially harmful effects are counterbalanced by the Agtr2 mediated signaling which promotes vasodilation, NO release and growth inhibition. AgtIII, resulting from the cleavage of AgtII by the aminopeptidase Enpep, engages the same two receptors with overall similar effects. Anpep, known as aminopeptidase N or M generates AgtIV from AgtIII. The leucyl/cystinyl aminopeptidase Lnpep, also known as Irap, has been shown to be the receptor for AngIV; AngIV triggered signaling is believed to play important roles in learning and memory. Finally, the Agt1-7 peptide can be generated from AgtII through the action of Ace2 or from AgtI through the action of the neutral endopeptidease Mme. Initially Agt1-7 was thought to be inactive but subsequent studies have shown that it signals through its own receptor Mas1 to mediate vasodilation and anti-proliferation and to exert endothelial functions. Malfunctioning of the RAS system has been associated with several conditions including cardiovascular and renal. diagram_image: https://rgd.mcw.edu/pathway/PW0000492/renin-angiotensin%20cascade%20pathway/pwmap.png pathway_studio_file: https://rgd.mcw.edu/pathway/PW0000492/renin-angiotensin%20cascade%20pathway/renin-angiotensin%20cascade%20pathway.gpp diagram_pathway_links: - id: PW:0000244 label: angiotensin II signaling pathway - id: PW:0000457 label: angiotensin III signaling pathway - id: PW:0000458 label: angiotensin IV signaling pathway - id: PW:0000527 label: angiotensin II signaling via AT1 receptor - id: PW:0000528 label: angiotensin II signaling via AT2 receptor - id: PW:0000529 label: angiotensin (1-7) signaling pathway - id: PW:0000530 label: angiotensin III signaling via AT1 receptor - id: PW:0000531 label: angiotensin III signaling via AT2 receptor diagram_gene_links: - id: RGD:2493 label: Ace - id: RGD:728890 label: Ace2 - id: RGD:2069 label: Agt - id: RGD:2070 label: Agtr1a - id: RGD:2071 label: Agtr1b - id: RGD:2072 label: Agtr2 - id: RGD:2991 label: Anpep - id: RGD:1561269 label: Atp6ap2 - id: RGD:2365 label: Cma1 - id: RGD:621228 label: Enpep - id: RGD:2871 label: Igf2r - id: RGD:621752 label: Lnpep - id: RGD:3049 label: Mas1 - id: RGD:3098 label: Mme - id: RGD:3554 label: Ren - id: RGD:621688 label: Renbp diagram_chemicals: - id: PUBCHEM.SUBSTANCE:26750209 label: Agt(1-7) - id: HMDB:HMDB01035 label: AgtII - id: HMDB:HMDB01036 label: AgtIII - id: HMDB:HMDB01038 label: AgtIV diagram_edges: - source: Agt relation: positively_affects target: AgtI - source: Agt(1-7) relation: associated_with target: Mas1 - source: AgtI relation: positively_affects target: Agt(1-7) - source: AgtI relation: positively_affects target: AgtII - source: AgtII relation: associated_with target: Agtr1a - source: AgtII relation: associated_with target: Agtr1b - source: AgtII relation: associated_with target: Agtr2 - source: AgtII relation: positively_affects target: Agt(1-7) - source: AgtII relation: positively_affects target: AgtIII - source: AgtIII relation: associated_with target: Agtr1a - source: AgtIII relation: associated_with target: Agtr1b - source: AgtIII relation: associated_with target: Agtr2 - source: AgtIII relation: positively_affects target: AgtIV - source: AgtIV relation: associated_with target: Lnpep - source: Atp6ap2 relation: associated_with target: Ren - source: Atp6ap2 relation: positively_affects target: renin receptor mediated intracellular signaling - source: Igf2r relation: associated_with target: Ren - source: Igf2r relation: positively_affects target: complex internalization - source: Ren relation: associated_with target: Renbp - source: Ren relation: positively_affects target: renin receptor mediated intracellular signaling - source: Renbp relation: negatively_affects target: Ren - source: angiotensin (1-7) signaling pathway relation: positively_affects target: vasodilation - source: angiotensin II signaling via AT1 receptor relation: positively_affects target: cell proliferation - source: angiotensin II signaling via AT1 receptor relation: positively_affects target: vasoconstriction - source: angiotensin II signaling via AT2 receptor relation: positively_affects target: vasodilation - source: angiotensin III signaling via AT1 receptor relation: positively_affects target: cell proliferation - source: angiotensin III signaling via AT1 receptor relation: positively_affects target: vasoconstriction - source: angiotensin III signaling via AT2 receptor relation: positively_affects target: vasodilation - source: angiotensin IV signaling pathway relation: positively_affects target: cognition diagram_labels: - AgtI - cell proliferation - cognition - complex internalization - vasoconstriction - vasodilation diagram_other_links: - href: /wg/home/pathway2/molecular-pathways2/renin-receptor-mediated-intracellular-signaling label: renin receptor mediated intracellular signaling references: - id: RGD:1581739 citation: Nguyen G, Kidney Int. 2006 May;69(9):1503-6. - id: RGD:1581742 citation: Leckie BJ Curr Med Chem Cardiovasc Hematol Agents. 2005 Jan;3(1):23-32. - id: RGD:1581849 citation: Reudelhuber TL Curr Opin Nephrol Hypertens. 2005 Mar;14(2):155-9. - id: RGD:5132613 citation: Takahashi S, etal., J Biochem. 2001 Dec;130(6):815-21. - id: RGD:5132617 citation: Nguyen G and Danser AH, Exp Physiol. 2008 May;93(5):557-63. Epub 2008 Mar 30. - id: RGD:5133657 citation: Nguyen G Ann Med. 2010;42(1):13-8. - id: RGD:5133658 citation: Nguyen G Clin Sci (Lond). 2011 Mar;120(5):169-78. - id: RGD:5133659 citation: Fyhrquist F and Saijonmaa O, J Intern Med. 2008 Sep;264(3):224-36. - id: RGD:5133660 citation: Bader M Annu Rev Pharmacol Toxicol. 2010;50:439-65.