Angiotensin‐(1‐7) inhibits sodium transport via Mas receptor by increasing nitric oxide production in thick ascending limb

• Published in: Physiological reports 2019-03, Vol.7 (5), p.e14015-n/a
• Main Authors: Dibo, Paula, Marañón, Rodrigo O., Chandrashekar, Kiran, Mazzuferi, Fernando, Silva, Guillermo B., Juncos, Luis A., Juncos, Luis I.
• Format: Article
• Language: English
• Subjects: Amiloride; Angiotensin; Angiotensin 1‐7; Angiotensin I - pharmacology; Angiotensin II; Animals; Biosynthesis; Blood pressure; Experiments; Furosemide; Heart failure; Homeostasis; Hypertension; Kidney; Kidneys; Laboratory animals; Loop of Henle; Loop of Henle - drug effects; Loop of Henle - metabolism; Male; mas receptor; Membrane Physiology; Natriuresis - drug effects; Natriuretic Agents - pharmacology; Nitric oxide; Nitric Oxide - metabolism; Original Research; Oxygen consumption; Oxygen Consumption - drug effects; Peptide Fragments - pharmacology; Physiology; Protein transport; Proto-Oncogene Proteins - agonists; Proto-Oncogene Proteins - metabolism; Rats, Wistar; Receptors, G-Protein-Coupled - agonists; Receptors, G-Protein-Coupled - metabolism; Renal Absorption, Reabsorption and Secretion; Renin; Signal Transduction; Sodium; Sodium - metabolism; TAL; Up-Regulation; Vasodilation
• ISSN: 2051-817X
• DOI: 10.14814/phy2.14015

Sodium transport in the thick ascending loop of Henle (TAL) is tightly regulated by numerous factors, especially angiotensin II (Ang II), a key end‐product of the renin‐angiotensin system (RAS). However, an alternative end‐product of the RAS, angiotensin‐(1‐7) [Ang‐(1‐7)], may counter some of the Ang II actions. Indeed, it causes vasodilation and promotes natriuresis through its effects in the proximal and distal tubule. However, its effects on the TAL are unknown. Because the TAL expresses the Mas receptor, an Ang‐(1‐7) ligand, which in turn may increase NO and inhibit Na+ transport, we hypothesized that Ang‐(1‐7) inhibits Na transport in the TAL, via a Mas receptor/NO‐dependent mechanism. We tested this by measuring transport‐dependent oxygen consumption (VO2) in TAL suspensions. Administering Ang‐(1‐7) decreased VO2; an effect prevented by dimethyl amiloride and furosemide, signifying that Ang‐(1‐7) inhibits transport‐dependent VO2 in TAL. Ang‐(1‐7) also increased NO levels, known inhibitors of Na+ transport in the TAL. The effects of Ang‐(1‐7) on VO2, as well as on NO levels, were ameliorated by the Mas receptor antagonist, D‐Ala, in effect suggesting that Ang‐(1‐7) may inhibit transport‐dependent VO2 in TAL via Mas receptor‐dependent activation of the NO pathway. Indeed, blocking NO synthesis with L‐NAME prevented the inhibitory actions of Ang‐(1‐7) on VO2. Our data suggest that Ang‐(1‐7) may modulate TAL Na+ transport via Mas receptor‐dependent increases in NO leading to the inhibition of transport activity. Our results show that Ang‐(1‐7) increases NO production in the TAL via activation of Mas receptors, thereby resulting in Ang‐(1‐7)‐induced inhibition of TAL transport‐related VO2. Also, it raises the possibility that Ang‐(1‐7) may play an important role in modulating sodium transport in the TAL and consequently natriuresis. Thus, novel therapies focused on modulating Ang‐(1‐7), its receptor, or signaling pathway, could potentially be beneficial in conditions in which increased excretion may be desired such as salt‐sensitive hypertension, or heart failure.