Renoprotective Effects of AVE0991, a Nonpeptide Mas Receptor Agonist, in Experimental Acute Renal Injury

Q: What are the key findings of this study?

AVE0991 (9.0 mg/kg) significantly attenuated serum creatinine elevation, renal and pulmonary neutrophil influx, serum CXCL1 levels, and histological renal injury in mice with renal I/R (P<0.05).

Q: What is the clinical evidence from this study?

Population: Experimental acute kidney injury induced by bilateral renal ischemia and reperfusion. Intervention: AVE0991 vs. Vehicle (10 mM KOH in 0.9% NaCl) or sham-operated controls treated with vehicle. Primary outcome: Renal function (serum creatinine), histological glomerular and tubular injury index, and neutrophil accumulation/CXCL1 levels at 24 hours after reperfusion (p=<0.05).

Q: What does this research mean for the field?

Pharmacological administration of the Mas receptor agonist AVE0991 attenuates acute renal ischemia/reperfusion injury by improving kidney function and suppressing systemic and local neutrophil infiltration and CXCL1 release. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

Q: What question did this study set out to answer?

To evaluate the renoprotective and anti-inflammatory effects of acute administration of the Mas receptor agonist AVE0991 in an experimental murine model of acute renal ischemia-reperfusion injury.

Lívia Corrêa Barroso; Kátia D. Silveira; Cristiano Xavier Lima; Valdinéria Borges; Michael Bäder; Milene Alvarenga Rachid; Robson A.S. Santos; Danielle G. Souza; Ana Cristina Simões e Silva; Mauro Martins Teixeira

doi:10.1155/2012/808726

January 1, 2012International Journal of HypertensionOpen Access

Renoprotective Effects of AVE0991, a Nonpeptide Mas Receptor Agonist, in Experimental Acute Renal Injury

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Key result

AVE0991 attenuates renal dysfunction, inflammation, and tissue injury in renal ischemia-reperfusion.

P<0.05

Why the study?

Does acute administration of AVE0991 improve renal function and reduce tissue inflammation and injury in a murine model of bilateral renal ischemia and reperfusion?

Key Points

To evaluate the renoprotective and anti-inflammatory effects of acute administration of the Mas receptor agonist AVE0991 in an experimental murine model of acute renal ischemia-reperfusion injury.
Subjected male C57BL/6 wild-type and Mas(-/-) mice to 30 minutes of bilateral renal ischemia followed by 24 hours of reperfusion.
Administered the nonpeptide Mas receptor agonist AVE0991 acutely to determine its effects on renal function, tissue histology, and inflammatory responses.
Treatment with AVE0991 attenuated the post-ischemic increase in serum creatinine and significantly decreased indices of both glomerular and tubular tissue damage compared to vehicle.
AVE0991 administration significantly reduced neutrophil influx in both renal and pulmonary tissues, accompanied by reduced circulating and tissue levels of the chemokine CXCL1.
Renal functional impairment and inflammatory neutrophil accumulation following ischemia-reperfusion did not differ between wild-type and Mas(-/-) mice.

Structured PICO

Does acute administration of AVE0991 improve renal function and reduce tissue inflammation and injury in a murine model of bilateral renal ischemia and reperfusion?

P

Population

Eight- to 10-week-old male C57BL/6 wild-type or Mas-/- mice weighing 20-25 g subjected to 30 minutes of bilateral renal ischemia and followed for 24 hours of reperfusion.

I

Intervention

AVE0991 (nonpeptide Mas receptor agonist) 9.0 mg/kg administered via subcutaneous injection (200 μL) immediately following 30 minutes of renal ischemia and at 12 hours after renal reperfusion.

C

Comparator

Vehicle (10 mM KOH in 0.9% NaCl) administered subcutaneously at the same time points, and sham-operated Mas+/+ mice treated with vehicle.

O

Outcome

Renal function impairment (serum creatinine, serum and urinary osmolality, osmolar and free-water clearance) and histological glomerular and tubular injury index (scored semiquantitatively 1 to 5 by blinded assessment) at 24 hours after reperfusion.surrogate

Main Result

p-value: p=<0.05

Pharmacological activation of the Mas receptor with the nonpeptide agonist AVE0991 provides renoprotective and anti-inflammatory effects in experimental acute kidney injury induced by ischemia-reperfusion, despite endogenous Mas deletion showing no baseline impact on injury severity.

Limitations

Cannot rule out the possibility that other mechanisms besides Mas receptor activation (such as ACE inhibition) could contribute to the beneficial effects of AVE0991.
Preclinical murine model requiring further investigation in the context of human disease.
Cannot rule out the possibility that other mechanisms (such as inhibiting renal ACE activity) could contribute to the beneficial effects of AVE0991
Preclinical animal model; findings require further investigation in the context of human disease

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Implication

Warrants caution before clinical translation; extends Mas receptor agonism as renoprotective target in experimental AKI.

Abstract

Renal ischemia and reperfusion (I/R) is the major cause of acute kidney injury in hospitalized patients. Mechanisms underlying reperfusion-associated injury include recruitment and activation of leukocytes and release of inflammatory mediators. In this study, we investigated the renal effects of acute administration of AVE0991, an agonist of Mas, the angiotensin-(1-7) receptor, the angiotensin-(1-7) receptor, in a murine model of renal I/R. Male C57BL/6 wild-type or Mas(-/-) mice were subjected to 30 min of bilateral ischemia and 24 h of reperfusion. Administration of AVE0991 promoted renoprotective effects, as seen by improvement of function, decreased tissue injury, prevention of local and remote leucocyte infiltration, and release of the chemokine, CXCL1. I/R injury was similar in WT and Mas(-/-) mice, suggesting that endogenous activation of this receptor does not control renal damage under baseline conditions. In conclusion, pharmacological interventions using Mas receptor agonists may represent a therapeutic opportunity for the treatment of renal I/R injury.

Discussion

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Cite This Study

Barroso et al. (2012) studied Experimental acute kidney injury induced by bilateral renal ischemia and reperfusion. AVE0991 vs. Vehicle (10 mM KOH in 0.9% NaCl) or sham-operated controls treated with vehicle was evaluated on Renal function (serum creatinine), histological glomerular and tubular injury index, and neutrophil accumulation/CXCL1 levels at 24 hours after reperfusion (p=<0.05). AVE0991 (9.0 mg/kg) significantly attenuated serum creatinine elevation, renal and pulmonary neutrophil influx, serum CXCL1 levels, and histological renal injury in mice with renal I/R (P<0.05).

synapsesocial.com/papers/6a773039f6b553d308ae5262 https://doi.org/10.1155/2012/808726

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Renoprotective Effects of AVE0991, a Nonpeptide Mas Receptor Agonist, in Experimental Acute Renal Injury

Key Points

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Renoprotective Effects of AVE0991, a Nonpeptide Mas Receptor Agonist, in Experimental Acute Renal Injury

Key Points

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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