Angiotensin-converting enzyme 2 mediates hyperfiltration associated with diabetes.

Area of Science:

• Nephrology
• Endocrinology
• Cardiovascular Research

Background:

• The renin-angiotensin-aldosterone system (RAAS) regulates blood pressure and fluid balance.
• Diabetic kidney disease is characterized by altered RAAS activity and hyperfiltration.
• Angiotensin-converting enzyme 2 (ACE2) degrades Angiotensin II (ANG II) to Angiotensin (1-7) [ANG(1-7)], modulating RAAS effects.

Purpose of the Study:

• To investigate the role of ACE2 in diabetic kidney hyperfiltration.
• To determine if ACE2 contributes to the increased renal reserve in diabetes.

Main Methods:

• Induction of diabetes using streptozotocin in wild-type and ACE2 knockout (KO) mice.
• Administration of a selective ACE2 inhibitor (MLN-4760) to diabetic mice.
• Micropuncture experiments to assess renal function and tubuloglomerular feedback.
• Evaluation of renal response to a high-protein diet.

Main Results:

• Diabetic wild-type mice exhibited increased renal ACE2 activity, hyperfiltration, and hypertrophy.
• ACE2 knockout and inhibition prevented diabetes-induced hyperfiltration and associated pressure changes.
• ACE2 inhibition did not acutely affect stop-flow pressure or tubuloglomerular feedback.
• ACE2 KO mice showed blunted creatinine clearance response to a high-protein diet.

Conclusions:

• ACE2 plays a crucial role in mediating renal hyperfiltration and recruiting renal reserve in diabetes.
• Targeting ACE2 may offer a therapeutic strategy for managing diabetic kidney complications.
• ACE2's contribution to renal reserve is significant, particularly in response to dietary challenges.