Podocyte-directed VEGFC gene therapy prevents increased glomerular permeability and glycocalyx damage in experimental...

Area of Science:

• Nephrology
• Genetics
• Vascular Biology

Background:

• Diabetic kidney disease (DKD) is a major cause of kidney failure.
• Current treatments do not effectively target the glomerulus, the primary site of DKD initiation.
• Vascular endothelial growth factor C (VEGF-C) plays a crucial role in maintaining glomerular endothelial barrier integrity.

Purpose of the Study:

• To investigate the therapeutic efficacy of podocyte-specific VEGF-C gene therapy in a mouse model of type 1 diabetic kidney disease.
• To determine if VEGF-C gene delivery can restore glomerular function and protect against DKD progression.

Main Methods:

• Adeno-associated virus serotype 9 (AAV2/9) vector was engineered to deliver human VEGF-C to podocytes.
• In vitro studies confirmed the functionality of expressed VEGF-C.
• Type 1 diabetes was induced in mice using streptozotocin.
• Systemic administration of AAV2/9 carrying VEGF-C was performed in diabetic mice.

Main Results:

• AAV2/9-mediated VEGF-C gene delivery increased glomerular VEGF-C expression in diabetic mice.
• The therapy significantly reduced albuminuria and glomerular permeability.
• VEGF-C gene therapy preserved the glomerular endothelial glycocalyx, a critical component of the filtration barrier.

Conclusions:

• Podocyte-directed VEGF-C gene delivery is a viable strategy for restoring glomerular function in early DKD.
• This novel gene therapy approach offers a promising therapeutic option for patients with type 1 diabetes at risk of DKD.
• The findings highlight the potential of targeting VEGF-C to address the unmet clinical need in DKD treatment.