Overexpression of angiotensinogen increases tubular apoptosis in diabetes

Area of Science:

• Nephrology
• Endocrinology
• Molecular Biology

Background:

• The intrarenal renin-angiotensin system (RAS) is implicated in diabetic nephropathy progression.
• Previous studies showed angiotensinogen overexpression in renal proximal tubular cells (RPTC) causes hypertension, albuminuria, and renal injury in mice.

Purpose of the Study:

• To investigate the role of intrarenal RAS activation in RPTC apoptosis during diabetes.
• To determine if high glucose and intrarenal RAS activation contribute to tubular apoptosis independently of systemic hypertension.

Main Methods:

• Streptozotocin-induced diabetes in transgenic mice overexpressing angiotensinogen in RPTC.
• Assessment of blood pressure, albuminuria, RPTC apoptosis, and proapoptotic gene expression.
• In vitro studies using high-glucose medium on rat immortalized RPTC overexpressing angiotensinogen.
• Treatment with insulin, RAS blockers, and hydralazine.

Main Results:

• Diabetic transgenic mice exhibited increased blood pressure, albuminuria, RPTC apoptosis, and proapoptotic gene expression compared to controls.
• Insulin and/or RAS blockers significantly attenuated these diabetic changes.
• Hydralazine normalized blood pressure but did not prevent albuminuria or RPTC apoptosis.
• In vitro, high glucose increased RPTC apoptosis and caspase-3 activity, which was reversed by insulin and RAS blockers.

Conclusions:

• Intrarenal RAS activation and high glucose synergistically promote tubular apoptosis in diabetes.
• This tubular apoptosis occurs independently of systemic hypertension.
• Targeting the intrarenal RAS may offer therapeutic benefits for diabetic nephropathy.