What is the clinical evidence from this study?

Study design: Other. Population: High-fat diet-induced kidney injury. Intervention: AT2R deletion (AT2KO) vs. Wild type (WT) mice. Primary outcome: Renal expression of RAS components and indices of kidney injury.

July 1, 2016Open Access

Angiotensin type 2 receptor null mice express reduced levels of renal angiotensin converting enzyme-2/angiotensin (1-7)/Mas receptor and exhibit greater high-fat diet-induced kidney injury

Key Result

Deletion of AT2R in mice decreased protective ACE2/Ang-(1-7)/MasR expression, increased the deleterious ACE/Ang II/AT1R axis, and exacerbated high-fat diet-induced renal injury.

Structured PICO

Does deletion of the angiotensin type 2 receptor increase susceptibility to high-fat diet-induced kidney injury in mice?

Population

AT2R knockout and wild type mice placed on a high-fat diet for 16 weeks to evaluate renal injury and RAS components.

Exposure

High fat diet (HFD) for 16 weeks

Comparator

Wild type (WT) mice on high fat diet

Outcome

Renal expression of RAS components and high fat diet-induced kidney injury (systolic blood pressure, mesangial matrix expansion score, microalbuminuria)surrogate

Deletion of the angiotensin type 2 receptor in mice exacerbates high-fat diet-induced kidney injury and shifts the renal renin-angiotensin system towards the deleterious ACE/Ang II/AT1R axis.

Abstract

INTRODUCTION: Renin-angiotensin system (RAS) components exert diverse physiological functions and have been sub-grouped into deleterious angiotensin-converting enzyme (ACE)/angiotensin II (Ang II)/angiotensin type 1 receptor (AT1R) and protective ACE2/angiotensin (1-7) (Ang-(1-7))/Mas receptor (MasR) axes. We have reported that chronic activation of angiotensin type 2 receptor (AT2R) alters RAS components and provides protection against obesity-related kidney injury. MATERIALS AND METHODS: We utilized AT2R knockout (AT2KO) mice in this study and evaluated the renal expression of various RAS components and examined the renal injury after placing these mice on high fat diet (HFD) for 16 weeks. RESULTS: The cortical ACE2 activity and MasR expression were significantly decreased in AT2KO mice compared to wild type (WT) mice. LC/MS analysis revealed an increase in renal Ang II levels and a decrease in Ang-(1-7) levels in AT2KO mice. Cortical expression of ACE and AT1R was increased but renin activity remained unchanged in AT2KO compared with WT mice. WT mice fed HFD exhibited increased systolic blood pressure, higher indices of kidney injury, mesangial matrix expansion score, and microalbuminuria, which were further increased in AT2KO mice. CONCLUSION: This study suggests that deletion of AT2R decreases the expression of the beneficial ACE2/Ang-(1-7)/MasR and increases the deleterious ACE/Ang II/AT1R axis of the renal RAS in mice. Further, AT2KO mice are more susceptible to HFD-induced renal injury.

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