Endothelin-a receptor blockade improves renal microvascular architecture and function in experimental...

Area of Science:

• Nephrology
• Cardiovascular Research
• Pharmacology

Background:

• Hypercholesterolemia (HC) can lead to early kidney injury by affecting renal microvessels (MV).
• The endothelin (ET) system is implicated in HC-related renal microcirculation changes, influencing MV tone and remodeling.
• ET-A receptor blockade is hypothesized to protect the kidney in HC by improving intrarenal MV function and mitigating damage.

Purpose of the Study:

• To investigate the renoprotective effects of ET-A receptor blockade in a porcine model of hypercholesterolemia.
• To assess the impact of ET-A blockade on renal microvessel architecture, function, and remodeling pathways in HC.

Main Methods:

• Experimental hypercholesterolemia (HC) was induced in pigs for 12 weeks.
• Pigs received either chronic ET-A receptor blocker (ABT-627) treatment or served as controls.
• Single-kidney function, hemodynamic responses, renal MV architecture (3D micro-CT), and growth factor expression were analyzed.

Main Results:

• HC kidneys exhibited increased MV density but impaired endothelial function compared to normal kidneys.
• ET-A blockade in HC pigs upregulated renal vascular growth factors, significantly increased MV density, and reduced tissue/MV remodeling.
• ET-A blockade improved MV endothelial function and reduced MV tortuosity, indicating enhanced neo-vessel maturation in HC kidneys.

Conclusions:

• The endogenous ET system plays a role in modulating renal MV architecture and function in hypercholesterolemia.
• ET-A blockade promotes renal MV proliferation and maturation, improves remodeling, and enhances function in the HC kidney.
• Targeting the ET pathway with ET-A blockers represents a promising renoprotective strategy for hypercholesterolemia and atherosclerosis.