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Notably, cilastatin competes with these drugs for binding to megalin. Patients with chronic kidney disease are at increased risk of contrast\u2010induced (CI) acute kidney injury, in which iodine\u2010mediated PTEC toxicity is a crucial pathogenic factor. This study investigated the interplay between megalin and CI\u2010PTEC injury, along with the protective effect of cilastatin, utilizing electron probe microanalysis, a mouse CI\u2010PTEC injury model, quartz crystal microbalance analysis, and binding assays with magnetic beads immobilized with iomeprol, a water\u2010soluble nonionic contrast medium (CM). Electron probe microanalysis revealed the reduced renal uptake of CMs\u00a0in the kidney cortex of kidney\u2010specific conditional megalin\u2010knockout mice compared with controls. In the CI\u2010PTEC injury model using kidney\u2010specific conditional or mosaic megalin\u2010knockout mice, a significant reduction of vacuolization was observed in PTECs in the cortex compared with controls in the former, while co\u2010expression of megalin and kidney injury molecule\u20101 was observed in the latter. These findings indicate that megalin is involved in the development of CI\u2010PTEC injury. Cilastatin inhibited the renal uptake of CMs and ameliorated CI\u2010PTEC injury in wild\u2010type mice. Of note, two distinct pathways of renal CM uptake were delineated, both of which cilastatin inhibited: the direct binding of CMs to megalin and an indirect route involving transcobalamin\u20102, an endocytic megalin ligand, functioning as a CM carrier. 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