Role of megalin and the soluble form of its ligand RAP in Cd-metallothionein endocytosis and Cd-metallothionein-induced nephrotoxicity in vivo

Onodera, Akira; Tani, Miyuki; Michigami, Toshimi; Yamagata, Masayo; Min, Kyung‐Jin; Tanaka, Keiichi; Nakanishi, Takashi; Kimura, Toshikiro; Itoh, Norio

doi:10.1016/j.toxlet.2012.05.012

Cited by 28 publications

(24 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Microinfusion of RAP along with gentamicin into rat proximal tubules blocked gentamicin uptake significantly and increased urinary excretion of gentamicin (55). In a cadmium-MT-induced AKI animal model, preinjection of soluble RAP decreased the accumulation of cadmium-MT and reduced kidney damage (61). Similarly, a decrease in the renal accumulation of gentamicin was observed in rats treated with gentamicin along with cytochrome c (90).…”

Section: Megalin In Akimentioning

confidence: 90%

“…Furthermore, megalin is a receptor for the PTEC uptake of heavy metal complexes by the binding of the heavy metal carrier protein metallothionein (MT) and plays a major role cadmium-MT-and zinc-MTinduced nephrotoxicity (40). Cadmium-MT-induced nephrotoxicity can be ameliorated by inhibition of megalin function (61). Megalin has also been shown to bind and mediate light chain uptake in the proximal tubule, inducing myeloma kidney disease (5,8,75).…”

Section: Megalin In Akimentioning

confidence: 99%

See 1 more Smart Citation

Megalin in acute kidney injury: foe and friend

Mahadevappa

Nielsen

Christensen

et al. 2014

American Journal of Physiology-Renal Physiology

View full text Add to dashboard Cite

The kidney proximal tubule is a key target in many forms of acute kidney injury (AKI). The multiligand receptor megalin is responsible for the normal proximal tubule uptake of filtered molecules, including nephrotoxins, cytokines, and markers of AKI. By mediating the uptake of nephrotoxins, megalin plays an essential role in the development of some types of AKI. However, megalin also mediates the tubular uptake of molecules implicated in the protection against AKI, and changes in megalin expression have been demonstrated in AKI in animal models. Thus, modulation of megalin expression in response to AKI may be an important part of the tubule cell adaption to cellular protection and regeneration and should be further investigated as a potential target of intervention. This review explores current evidence linking megalin expression and function to the development, diagnosis, and progression of AKI as well as renal protection against AKI.

show abstract

Section: Megalin In Akimentioning

confidence: 90%

Section: Megalin In Akimentioning

confidence: 99%

Megalin in acute kidney injury: foe and friend

Mahadevappa

Nielsen

Christensen

et al. 2014

American Journal of Physiology-Renal Physiology

View full text Add to dashboard Cite

show abstract

“…Much attention has focused on the identification of urinary biomarkers of the early stages of Cd nephrotoxicity, such as metallothionein (Dorian et al ; Nordberg et al ; Onodera et al ). Metallothionein is a specific metal‐binding protein that plays a role in concentrating Cd in the PT epithelium (Dorian et al ; Nordberg et al ; Onodera et al ). Although the adult medaka kidney has fewer nephrons, the structural units of the kidney, and a less complex overall structure, the basic renal structure and function are largely conserved between medaka and mammalian kidney (2; Wessely and Obara ; Walter and Obara ).…”

Section: Resultsmentioning

confidence: 99%

“…Cd causes a generalized dysfunction of the proximal tubule (PT) that is characterized by polyuria and proteinuria (Lane et al 2015;Aoshima 2016). Much attention has focused on the identification of urinary biomarkers of the early stages of Cd nephrotoxicity, such as metallothionein (Dorian et al 1992;Nordberg et al 2007;Onodera et al 2012). Metallothionein is a specific metal-binding protein that plays a role in concentrating Cd in the PT epithelium (Dorian et al 1992;Nordberg et al 2007;Onodera et al 2012).…”

Section: Exposure Conditions To Study the Xenobiotic Pathotoxicitymentioning

confidence: 99%

Extracellular vesicles from human bone marrow mesenchymal stem cells repair organ damage caused by cadmium poisoning in a medaka model

et al. 2019

View full text Add to dashboard Cite

Treatment modalities for kidney disease caused by long‐term exposure to heavy metals, such as cadmium (Cd), are limited. Often, chronic, long‐term environmental exposure to heavy metal is not recognized in the early stages; therefore, chelation therapy is not an effective option. Extracellular vesicles (EVs) derived from stem cells have been demonstrated to reduce disease pathology in both acute and chronic kidney disease models. To test the ability of EVs derived from human bone marrow mesenchymal stem cells (hBM‐MSCs) to treat Cd damage, we generated a Cd‐exposed medaka model. This model develops heavy metal‐induced cell damage in various organs and tissues, and shows decreased overall survival. Intravenous injection of highly purified EVs from hBM‐MSCs repaired the damage to apical and basolateral membranes and mitochondria of kidney proximal tubules, glomerular podocytes, bone deformation, and improved survival. Our system also serves as a model with which to study age‐ and sex‐dependent cell injuries of organs caused by various agents and diseases. The beneficial effects of EVs on the tissue repair process, as shown in our novel Cd‐exposed medaka model, may open new broad avenues for interventional strategies.

show abstract

“…In another study, RAP at 1 µM in the medium only partially inhibited megalin-dependent internalization of cadmium-metallothionein (by 30.9±6.6%) although this was sufficient to avert cadmium cytotoxicity in cultured renal proximal tubule cells [20]. More recently, inhibition of cadmium-metallothionein endocytosis by RAP in kidney proximal tubule cells was also shown to reduce the toxic effects of cadmium on the kidney in mice in vivo [29]. RAP may affect endocytosis in other receptor systems as well, as it was recently shown to inhibit sortilin and mannose-6- receptor mediated endocytosis of alpha-galactosidase in renal endothelial cells in vitro [30].…”

Section: Discussionmentioning

confidence: 97%

Receptor-Associated Protein Blocks Internalization and Cytotoxicity of Myeloma Light Chain in Cultured Human Proximal Tubular Cells

et al. 2013

View full text Add to dashboard Cite

BackgroundFree light chains (LCs) are among the many ligands that bind to cubilin/megalin for endocytosis via the clathrin-dependent endosomal/lysosomal pathway. Receptor associated protein (RAP), is a 39 kDA high-affinity, chaperone-like ligand for megalin that assists in the proper folding and functioning of megalin/cubilin. Although RAP is known to inhibit ligand binding to megalin/cubilin, its effect on LC endocytosis has not been shown directly.Methods and Principal FindingsWe investigated whether RAP can block the endocytosis of LC in cultured human proximal tubule cells and whether this can prevent LC cytotoxicity. Immunofluorescence microscopy and flow cytometry showed that fluorescently labeled LC endocytosis was markedly inhibited in HK-2 cells pretreated with human RAP. The effect of RAP was dose-dependent, and was predominantly on endocytosis as it had no effect on the small acid-washable fraction of LC bound to cell membrane. RAP significantly inhibited LC induced cytokine production and phosphorylation of ERK1/2 and p38 MAPK. Prolonged exposure to LC for 48 h resulted in epithelial-to-mesenchymal transformation in HK-2 cells as evidenced by marked reduction in the expression of the epithelial cell marker E-cadherin, and increased the expression of the mesenchymal marker α-SMA, which was also prevented by RAP in the endocytosis medium.ConclusionsRAP inhibited LC endocytosis by ∼88% and ameliorated LC-induced cytokine responses and EMT in human PTCs. The results not only provide additional evidence that LCs endocytosis occurs via the megalin/cubilin endocytic receptor system, but also show that blocking LC endocytosis by RAP can protect proximal tubule cells from LC cytotoxicity.

show abstract

Role of megalin and the soluble form of its ligand RAP in Cd-metallothionein endocytosis and Cd-metallothionein-induced nephrotoxicity in vivo

Cited by 28 publications

References 30 publications

Megalin in acute kidney injury: foe and friend

Megalin in acute kidney injury: foe and friend

Extracellular vesicles from human bone marrow mesenchymal stem cells repair organ damage caused by cadmium poisoning in a medaka model

Receptor-Associated Protein Blocks Internalization and Cytotoxicity of Myeloma Light Chain in Cultured Human Proximal Tubular Cells

Contact Info

Product

Resources

About