title: Role of megalin and the soluble form of its ligand RAP in Cd-metallothionein endocytosis and Cd-metallothionein-induced nephrotoxicity in vivo.
abstract: Orally administered Cd is predominantly distributed to the intestine, and the majority of this mucosal Cd is bound to metallothionein (MT). MT attenuates heavy metal-induced cytotoxicity by sequestering these metals and lowering their intracellular concentrations. In addition, MT acts as an extracellular transporter of orally administered Cd to the kidney. Because of its low molecular weight, the Cd-MT complex is freely filtered at the glomerulus, and the filtered Cd-MT is then incorporated into renal proximal tubular cells. Megalin, a multiligand endocytic receptor (also known as low-density lipoprotein receptor-related protein 2 or Lrp2), acts as the receptor for Cd-MT in a renal proximal tubular cell model. Here, we used the soluble form of 39-kDa receptor-associated protein (sRAP; also known as Lrpap1), a ligand of megalin, to inhibit megalin function, and then analyzed the effect of megalin loss on Cd-MT distribution and Cd-MT-induced nephrotoxicity in an animal model. Administration of sRAP to mice caused acute loss of megalin function by removing megalin in the brush border membrane. The pre-injection of sRAP decreased renal Cd content and decreased Cd-MT-induced kidney damage. Our results demonstrate that sRAP reduces Cd-MT-induced kidney toxicity in vivo.
authors.affiliation: Department of Toxicology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Onodera
authors.forename: Miyuki
authors.initials: M
authors.lastname: Tani
authors.forename: Toshimi
authors.initials: T
authors.lastname: Michigami
authors.forename: Masayo
authors.initials: M
authors.lastname: Yamagata
authors.forename: Kyong-Son
authors.initials: KS
authors.lastname: Min
authors.forename: Keiichi
authors.initials: K
authors.lastname: Tanaka
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Nakanishi
authors.forename: Tomoki
authors.initials: T
authors.lastname: Kimura
authors.forename: Norio
authors.initials: N
authors.lastname: Itoh
mesh_terms: D000818:Animals; D004705:Endocytosis; D007668:Kidney / Q000187:drug effects*; D026563:LDL-Receptor Related Protein-Associated Protein / Q000502:physiology*; D008024:Ligands; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000502:physiology*; D008297:Male; D008668:Metallothionein / Q000493:pharmacokinetics / Q000633:toxicity*; D051379:Mice; D008813:Mice, Inbred ICR
chemical_list: D026563:LDL-Receptor Related Protein-Associated Protein; D008024:Ligands; D026561:Low Density Lipoprotein Receptor-Related Protein-2; C055127:Lrp2 protein, mouse; C004203:cadmium-binding protein; D008668:Metallothionein