Megalin-Mediated Direct and Indirect Pathways for the Development of Contrast-Induced Proximal Tubule Epithelial Cell...

Area of Science:

• Nephrology
• Cell Biology
• Toxicology

Background:

• Megalin is an endocytic receptor in kidney proximal tubule epithelial cells (PTECs) involved in reabsorbing substances.
• Contrast-induced (CI) acute kidney injury is a risk in chronic kidney disease patients, with PTEC toxicity being a key factor.
• Cilastatin is known to compete with certain drugs for megalin binding.

Purpose of the Study:

• To investigate the role of megalin in CI-PTEC injury.
• To evaluate the protective effect of cilastatin against CI-PTEC injury.
• To elucidate the mechanisms of contrast medium (CM) uptake and inhibition by cilastatin.

Main Methods:

• Utilized kidney-specific conditional megalin-knockout mice and mosaic megalin-knockout mice.
• Employed electron probe microanalysis, quartz crystal microbalance analysis, and magnetic bead binding assays.
• Established a mouse model for CI-PTEC injury.

Main Results:

• Reduced renal uptake of CMs was observed in megalin-knockout mice.
• Megalin-knockout mice showed significantly less PTEC vacuolization following CI injury.
• Cilastatin inhibited CM renal uptake and ameliorated CI-PTEC injury in wild-type mice.
• Two CM uptake pathways were identified: direct binding to megalin and an indirect route via transcobalamin-2, both inhibited by cilastatin.

Conclusions:

• Megalin is implicated in the development of CI-PTEC injury through direct and indirect CM uptake pathways.
• Cilastatin effectively inhibits both direct and indirect CM uptake pathways, offering protection against CI-PTEC injury.