Genetic deletion of the angiotensin-(1–7) receptor Mas leads to glomerular hyperfiltration and microalbuminuria

Abstract

Angiotensin-(1-7), an active fragment of both angiotensins I and II, generally opposes the vascular and proliferative actions of angiotensin II. Here we evaluated effects of the angiotensin-(1-7) receptor Mas on renal physiology and morphology using Mas-knockout mice. Compared to the wild-type animals, Mas knockout mice had significant reductions in urine volume and fractional sodium excretion without any significant change in free-water clearance. A significantly higher inulin clearance and microalbuminuria concomitant with a reduced renal blood flow suggest that glomerular hyperfiltration occurs in the knockout mice. Histological analysis found reduced glomerular tuft diameter and increased expression of collagen IV and fibronectin in the both the mesangium and interstitium, along with increased collagen III in the interstitium. These fibrogenic changes and the renal dysfunction of the knockout mice were associated with an upregulation of angiotensin II AT1 receptor and transforming growth factor-beta mRNA. Our study suggests that Mas acts as a critical regulator of renal fibrogenesis by controlling effects transduced through angiotensin II AT1 receptors in the kidney.

Angiotensin-(1-7) Reduces Fibrosis in Orthotopic Breast Tumors

“…Studies by our group showed that Ang-(1-7) infusion reduced cardiac fibrosis in Ang IItreated rats, further illustrating the role of Ang-(1-7) as an antifibrotic agent (47). Mice with ablated mas, the Ang-(1-7) receptor, have impaired cardiac function with increased cardiac collagen I, collagen III, and fibronectin deposition (48), whereas mas deletion increased collagen III, collagen IV, and fibronectin in the renal cortex and medulla (49). Our results show that Ang-(1-7), through activation of mas, also inhibits tumoral fibrosis.…”

Angiotensin-converting enzyme 2, angiotensin-(1–7) and Mas: new players of the renin–angiotensin system

“…Besides its physiological relevance for kidney homeostasis, the ACE2/Ang-(1-7)/Mas axis also has an important and controversial role in renal diseases, acting as a renoprotective (Oudit et al 2006, 2010, Soler et al 2007, Pinheiro et al 2009, Burns et al 2010, Dilauro et al 2010, Zhang et al 2010, Giani et al 2011, Liu et al 2011b, Moon et al 2011, Stegbauer et al 2011, Zhong et al 2011, Barroso et al 2012, Kim et al 2012, Nadarajah et al 2012 or a proinflammatory (Esteban et al 2009, Velkoska et al 2011 agent. Briefly, Pinheiro et al (2009) reported that mice with genetic deletion of Mas developed renal dysfunction with an increase of glomerular tuft diameter and enhancement of fibronectin and collagen IV and III deposition, besides an increase of AT 1 and TGF-b expression.…”

“…Briefly, Pinheiro et al (2009) reported that mice with genetic deletion of Mas developed renal dysfunction with an increase of glomerular tuft diameter and enhancement of fibronectin and collagen IV and III deposition, besides an increase of AT 1 and TGF-b expression. Moreover, Ang-(1-7) infusion counterregulates Ang II to reduce glomerulosclerosis in experimental glomerulonephritis (Zhang et al 2010).…”

ACE2–angiotensin-(1–7)–Mas axis and oxidative stress in cardiovascular disease

“…9 It has been suggested that Ang-(1-7) mediates its effects by interacting with the G-proteincoupled receptor Mas, 10 a prototypic seven-transmembrane domain receptor (Figure 1), which is predominantly expressed in the brain and testis 11 but is also found in the kidney, heart and vessels. [11][12][13] Moreover, several studies have shown that the interaction of Ang-(1-7) with Mas evokes numerous protective cardiovascular actions, such as nitric oxide ( NO) 14,15 release, Akt phosphorylation 16 and vasodilation ( Figure 2). 17 Nevertheless, other studies indicate that Ang-(1-7) may function through angiotensin type 2 receptor 18 and that Mas can antagonize the actions of the angiotensin type 1 receptor.…”