Angiotensin-(1-7): A Novel Peptide to Treat Hypertension and Nephropathy in Diabetes?

Abstract

The renin-angiotensin system (RAS) plays a pivotal role in mammalian homeostasis physiology. The RAS can be delineated into a classical RAS (the pressor arm) including angiotensinogen (Agt), renin, angiotensin-converting enzyme (ACE), angiotensin II (Ang II) and angiotensin type 1 receptor (AT1R), and a counterbalancing novel RAS (the depressor arm) including Agt, renin, angiotensin-converting enzyme-2 (ACE-2), angiotensin-(1-7) (Ang 1-7) and Ang 1-7 receptor (or Mas receptor (MasR)). Hyperglycemia (diabetes) induces severe tissue oxidative stress, which stimulates the pressor arm of the renal RAS axis and leads to an increase in ACE/ACE-2 ratio, with excessive formation of Ang II. There is a growing body of evidence for beneficial effects of the depressor arm of RAS (ACE-2/Ang 1-7/MasR) axis in diabetes, hypertension and several other diseased conditions. Evidence from in vitro, in vivo and clinical studies reflects anti-oxidant, antifibrotic, and anti-inflammatory properties of Ang 1-7. Most of the currently available therapies only target suppression of the pressor arm of RAS with angiotensin receptor blockers (ARBs) and ACE inhibitors (ACEi). However, it is time to consider simultaneous activation of the depressor arm for more effective outcomes. This review summarizes the recent updates on the protective role of Ang 1-7 in hypertension and kidney injury in diabetes, as well as the possible underlying mechanism(s) of Ang 1-7 action, suggesting that the ACE-2/Ang 1-7/MasR axis can be developed as a therapeutic target for the treatment of diabetes-induced hypertension and renal damage.

Angiotensin‐(1–7) protects cardiomyocytes against high glucose‐induced injuries through inhibiting reactive oxygen species‐activated leptin–p38 mitogen‐activated protein kinase/extracellular signal‐regulated protein kinase 1/2 pathways, but not the leptin–c‐Jun N‐terminal kinase pathway in vitro

“…Recently, numerous scientific researchers have proved the extensive physiological and pathophysiological properties of Ang-(1-7) on the progress of diabetes. Previous findings have shown that Ang-(1-7) functions in reducing systematic hypertension, oxidation, fibrosis and inflammation 21 . However today, the beneficial effects of Ang-(1-7), as a protection opposition to HG-stimulated injuries, are still unclear.…”

SGLT2 Inhibitors as a Therapeutic Option for Diabetic Nephropathy

“…However, RAAS activation during ACE inhibition or angiotensin-receptor blockade may favor the renoprotective effects of the RAAS cascade, including angiotensin 1–7 (Ang-1–7) production and the activation of type-2-angiotensin-II receptor (AT 2 R) and Mas receptors (MasR) [69]. In contrast to the pressor arm of the RAAS (angiotensin-II–AT 1 R axis), a significant body of evidence has shown that the depressor arm (Ang-1–7–MasR) axis exerts beneficial effects against DN [70]. Ang-1–7, which is produced from angiotensin-II by ACE2, is a heptapeptide found in the heart and kidneys and a specific ligand for MasR that has anti-inflammatory, antioxidative stress, and vasodilatory effects [71].…”

Effects of sodium glucose co-transporter 2 inhibitors on the kidney

“…[46][47][48] In addition, through the Mas receptor, angiotensin-(1-7) has been shown to reduce signalling pathways thought to be responsible to fibrogenesis and chronic inflammation. 49 Animal studies have shown an additive benefit of SGLT2i to angiotensin-converting enzyme inhibitors (ACEi) in slowing the progression of diabetic nephropathy 50 and lowering BP, [51][52][53] an effect that might be linked to upregulation of the non-classical pathway.…”