Molecular and Cellular Approaches Toward Understanding the Role of Lysosomes in Gadolinium-Based Contrast Agent Nephrotoxicity

Modern MRI contrast agents utilize gadolinium (Gd3+), a heavy metal of the lanthanide series. Gd3+ has remarkable paramagnetic properties, but it is inherently toxic. The most outstanding finding from our first study is the development of electron-dense intracellular precipitates in animal and human kidneys, which were abundant in gadolinium and phosphorus. This suggests that dissociation of gadolinium from the ligand plays a role in developing renal pathologies. Given the morphological findings in vivo, the second study focused on identifying molecular and cellular targets of GBCAs in a culture model of renal proximal tubule epithelial cells. GBCAs hijack the endolysosomal system, leading to early lysosomal injury and dysfunction. GBCA exposure results in time-dependent permeabilization of the lysosomal membrane, and the selective release of cathepsins impacts mitochondrial integrity and function. The results from both studies implicate lysosomes in the pathogenesis of GBCA nephrotoxicity and justify follow-up studies to discover potential mitigation therapies.