RAS blockade decreases blood pressure and proteinuria in transgenic mice overexpressing rat angiotensinogen gene in...

Area of Science:

• Nephrology
• Cardiovascular Research
• Molecular Biology

Background:

• The renin-angiotensin system (RAS) plays a crucial role in regulating blood pressure.
• RAS activation is linked to hypertension and subsequent cardiovascular and renal damage.
• Intrarenal RAS mechanisms contributing to hypertension-induced nephropathy require further elucidation.

Purpose of the Study:

• To investigate if intrarenal RAS activation, driven by angiotensinogen (ANG) overexpression in the kidney, can independently cause hypertension and renal injury.
• To determine if RAS blockade can ameliorate hypertension and kidney damage induced by intrarenal ANG overproduction.

Main Methods:

• Generation of transgenic mice with kidney-specific overexpression of rat ANG (rANG) using an androgen-regulated promoter.
• Assessment of blood pressure (BP), albuminuria, and renal histopathology in transgenic and non-transgenic mice.
• Evaluation of the effects of losartan (angiotensin II type 1 receptor antagonist) and perindopril (angiotensin-converting enzyme inhibitor) on BP and renal parameters.

Main Results:

• Transgenic mice exhibited kidney-specific rANG expression, elevated BP, and increased albuminuria compared to controls.
• Renal injury was observed in transgenic mice.
• Treatment with losartan or perindopril reversed the elevated BP, albuminuria, and renal injury in transgenic mice.

Conclusions:

• Intrarenal ANG overproduction alone is sufficient to induce systemic hypertension, proteinuria, and renal damage.
• RAS blockade effectively prevents and reverses these hypertension- and kidney injury-related abnormalities.
• These findings underscore the critical role of the intrarenal RAS in the pathogenesis of hypertension and renal disease.