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

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 (AT(1)R) and protective ACE2/angiotensin (1-7) (Ang-(1-7))/Mas receptor (MasR) axes. We have reported that chronic activation of angiotensin type 2 receptor (AT(2)R) alters RAS components and provides protection against obesity-related kidney injury. MATERIALS AND METHODS: We utilized AT(2)R knockout (AT(2)KO) 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 AT(2)KO 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 AT(2)KO mice. Cortical expression of ACE and AT(1)R was increased but renin activity remained unchanged in AT(2)KO 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 AT(2)KO mice. CONCLUSION: This study suggests that deletion of AT(2)R decreases the expression of the beneficial ACE2/Ang-(1-7)/MasR and increases the deleterious ACE/Ang II/AT(1)R axis of the renal RAS in mice. Further, AT(2)KO mice are more susceptible to HFD-induced renal injury.