Beneficial Effects of the Activation of the Angiotensin-(1–7) Mas Receptor in a Murine Model of Adriamycin-Induced Nephropathy

Abstract

Angiotensin-(1–7) [Ang-(1–7)] is a biologically active heptapeptide that may counterbalance the physiological actions of angiotensin II (Ang II) within the renin-angiotensin system (RAS). Here, we evaluated whether activation of the Mas receptor with the oral agonist, AVE 0991, would have renoprotective effects in a model of adriamycin (ADR)-induced nephropathy. We also evaluated whether the Mas receptor contributed for the protective effects of treatment with AT1 receptor blockers. ADR (10 mg/kg) induced significant renal injury and dysfunction that was maximal at day 14 after injection. Treatment with the Mas receptor agonist AVE 0991 improved renal function parameters, reduced urinary protein loss and attenuated histological changes. Renoprotection was associated with reduction in urinary levels of TGF-β. Similar renoprotection was observed after treatment with the AT1 receptor antagonist, Losartan. AT1 and Mas receptor mRNA levels dropped after ADR administration and treatment with losartan reestablished the expression of Mas receptor and increased the expression of ACE2. ADR-induced nephropathy was similar in wild type (Mas+/+) and Mas knockout (Mas −/−) mice, suggesting there was no endogenous role for Mas receptor activation. However, treatment with Losartan was able to reduce renal injury only in Mas+/+, but not in Mas −/− mice. Therefore, these findings suggest that exogenous activation of the Mas receptor protects from ADR-induced nephropathy and contributes to the beneficial effects of AT1 receptor blockade. Medications which target specifically the ACE2/Ang-(1–7)/Mas axis may offer new therapeutic opportunities to treat human nephropathies.

Anti‐atherosclerotic effect of the angiotensin 1–7 mimetic AVE0991 is mediated by inhibition of perivascular and plaque inflammation in early atherosclerosis

“…Lack of effect of AVE0991 on PVAT leukocyte infiltration in the control group may also indicate different mechanisms being involved in the regulation of leukocyte accumulation in control and atherosclerotic conditions. Ang‐(1‐7) and the synthetic Mas receptor agonist AVE 0991 have been effective in a number of inflammatory models, such as arthritis (da Silveira et al , ), asthmatic lung inflammation (Rodrigues‐Machado et al , ) and renal inflammation (Silveira et al , ).…”

Pathophysiological Mechanisms of Renal Fibrosis: A Review of Animal Models and Therapeutic Strategies

“…Adriamycin induced rat nephropathy with massive proteinuria, tubular basement membrane lesions, probably causing an inflammatory response and interstitial fibrosis (4). Adriamycin administration at a dosage of 10 mg/kg for each mouse by means of a single intravenous tail-vein injection causes proteinuria, glomerular and podocyte injury, followed by tubular atrophy and finally renal fibrosis (53)(54)(55). In a study with BALB/c mice, proteinuria was verified on day 5 and at higher levels on day 7; after weeks 1 and 2 glomerular and tubular lesions were observed, and by week 4 these changes were more evident.…”

Diabetic Kidney Disease in Adolescents With Type 2 Diabetes: New Insights and Potential Therapies

“…In fact, DKD is associated with reduced tubular ACE2 expression (124) and ACE2 activity is associated with glycemic control and glomerular filtration rate (GFR) in adults with DKD (125). For these reasons, studies have investigated ACE2 as a potential therapeutic target using recombinant ACE2 and Mas receptor modulators to diminish DKD progression, with promising preliminary results (126–130). …”