Glomerular structure and function require paracrine, not autocrine, VEGF-VEGFR-2 signaling

Area of Science:

• Nephrology
• Molecular Biology
• Cell Biology

Background:

• Vascular Endothelial Growth Factor (VEGF) is produced by podocytes and is critical for glomerular filtration barrier (GFB) integrity.
• Paracrine VEGF signaling from podocytes to endothelial cells is essential for GFB maintenance.
• The role of autocrine VEGF signaling within podocytes for GFB function remains unclear.

Purpose of the Study:

• To investigate the role of the autocrine VEGF-VEGFR-2 signaling loop in podocytes for maintaining the glomerular filtration barrier in vivo.
• To determine whether podocyte-specific deletion of VEGFR-2 impacts glomerular development and function.
• To elucidate the specific contributions of VEGF-VEGFR-2 signaling in podocytes versus glomerular endothelial cells.

Main Methods:

• Utilized inducible, whole-body deletion models for VEGFR-2.
• Generated podocyte-specific VEGFR-2 knockout mice.
• Administered enhanced VEGF expression in podocytes and inhibited VEGFR-2.
• Performed postnatal deletion of VEGFR-2 in glomerular endothelial cells.

Main Results:

• Whole-body VEGFR-2 deletion led to severe kidney, heart, and liver abnormalities.
• Podocyte-specific deletion of VEGFR-2 did not affect glomerular development or function.
• Enhanced podocyte VEGF expression caused foot process fusion and altered slit diaphragm proteins, independent of VEGFR-2 inhibition.
• Glomerular endothelial cells critically depend on VEGFR-2 for microvasculature development.

Conclusions:

• A paracrine VEGF-VEGFR-2 signaling loop is dominant in regulating glomerular structure and function.
• Podocyte-derived VEGF primarily acts on adjacent endothelial cells via VEGFR-2.
• Autocrine signaling through VEGFR-2 within podocytes is dispensable for maintaining the glomerular filtration barrier.