Increased Endocytosis of Cadmium-Metallothionein through the 24p3 Receptor in an In Vivo Model with Reduced Proximal Tubular Activity

Abstract

Background: The proximal tubule (PT) is the major target of cadmium (Cd2+) nephrotoxicity. Current dogma postulates that Cd2+ complexed to metallothionein (MT) (CdMT) is taken up through receptor-mediated endocytosis (RME) via the PT receptor megalin:cubilin, which is the predominant pathway for reuptake of filtered proteins in the kidney. Nevertheless, there is evidence that the distal parts of the nephron are also sensitive to damage induced by Cd2+. In rodent kidneys, another receptor for protein endocytosis, the 24p3 receptor (24p3R), is exclusively expressed in the apical membranes of distal tubules (DT) and collecting ducts (CD). Cell culture studies have demonstrated that RME and toxicity of CdMT and other (metal ion)–protein complexes in DT and CD cells is mediated by 24p3R. In this study, we evaluated the uptake of labeled CdMT complex through 24p3R after acute kidney injury (AKI) induced by gentamicin (GM) administration that disrupts PT function. Subcutaneous administration of GM at 10 mg/kg/day for seven days did not alter the structural and functional integrity of the kidney’s filtration barrier. However, because of PT injury, the concentration of the renal biomarker Kim-1 increased. When CdMT complex coupled to FITC was administered intravenously, both uptake of the CdMT complex and 24p3R expression in DT increased and also colocalized after PT injury induced by GM. Although megalin decreased in PT after GM administration, urinary protein excretion was not changed, which suggests that the increased levels of 24p3R in the distal nephron could be acting as a compensatory mechanism for protein uptake. Altogether, these results suggest that PT damage increases the uptake of the CdMT complex through 24p3R in DT (and possibly CD) and compensate for protein losses associated with AKI.

Effects of cadmium acetate contaminated drinking water on vital organs: A histopathological and biochemical study

“…MT protein has also been reported to provide a protective response against Cd in the body, so increased expression is the body's response to decrease Cd toxicity. [38] A biochemical study was performed to check the functions of significant fluctuation in all groups. High creatinine levels were observed in Cd treated group.…”

“…MT protein has also been reported to provide a protective response against Cd in the body, so increased expression is the body's response to decrease Cd toxicity. [ 38 ]…”

Using Peromyscus leucopus as a biomonitor to determine the impact of heavy metal exposure on the kidney and bone mineral density: results from the Tar Creek Superfund Site

“…Elimination of cadmium by the kidneys is slow. Chronic exposures to cadmium ions can result in proteinuria and tubular dysfunction in the proximal tubules ( Davenport, 2020 ; Godt et al, 2006 ; Yan & Allen, 2021 ; Zavala-Guevara et al, 2021 ). Renal toxicity from cadmium exposure is correlated with the number of cadmium ions in kidney tubule cells, reabsorption, degradation of cadmium metallothionein complexes, and excess production of metallothionein by renal tubules ( Davenport, 2020 ; Zavala-Guevara et al, 2021 ).…”

“…Chronic exposures to cadmium ions can result in proteinuria and tubular dysfunction in the proximal tubules ( Davenport, 2020 ; Godt et al, 2006 ; Yan & Allen, 2021 ; Zavala-Guevara et al, 2021 ). Renal toxicity from cadmium exposure is correlated with the number of cadmium ions in kidney tubule cells, reabsorption, degradation of cadmium metallothionein complexes, and excess production of metallothionein by renal tubules ( Davenport, 2020 ; Zavala-Guevara et al, 2021 ). Cadmium toxicity observed in the renal cortex of laboratory rats ( Rattus rattus ) resulted in cytosolic damage and renal malfunction after oral administration of cadmium chloride (CdCl 2 ) ( Alimba et al, 2021 ; Hashim et al, 2018 ; Siddiqui, 2010 ).…”

Editorial to Special Issue Toxic Metals, Chronic Diseases and Related Cancers

“…A question remains with regard to the specificity of this cadmium effect. A recent study suggested that reabsorption of β 2 MG and MT may occur mainly at the distal tubule and collecting duct, where other receptor-mediated endocytosis systems are expressed [ 20 ].…”