Hyperglycemia exacerbates cadmium-induced glomerular nephrosis

Abstract

Current research suggests that cadmium (Cd) exposure may be associated with the progression of diabetic nephropathy; however, the details of this relationship are insufficiently understood. The present study investigated the effects of elevated glucose on Cd-induced toxicity to glomerular cells using in vitro and in vivo models, and it demonstrated that Cd exposure and the hyperglycemia of diabetes acting together increased the risk of developing glomerular nephrosis . In vitro, human podocytes were exposed to a DMEM low-glucose media without (control), or with Cd (as CdCl2), or a high-glucose media plus Cd. The CCK-8, ROS, apoptosis, and mitochondrial transmembrane potential (ΔΨm) assays showed that human podocytes exposed to Cd in a high-glucose media had greater degrees of injury compared with cells treated with Cd at low (euglycemic)-glucose levels. In vivo, diabetic hyperglycemia was induced by streptozotocin in 8-week-old male C57BL/6 mice to which either CdCl2 or saline (control) was intraperitoneally injected twice weekly for 24 weeks. Compared with euglycemic saline-treated controls, the diabetic mice exposed to Cd demonstrated decreased body weight and increased blood urea nitrogen levels along with histopathological renal architecture changes including collagen fiber accumulation. The results of this study supported the hypothesis that hyperglycemia plus Cd exposure increases the risk of damage to glomerular podocytes compared with Cd exposure in euglycemia.

Molecular Mechanisms of Cellular Injury and Role of Toxic Heavy Metals in Chronic Kidney Disease

“…This variation could be due to differences in the frequency and dose of Cd exposure. This study, however, confirmed findings that exposure of hyperglycemic animals to Cd enhances the risk of renal injury [ 138 ]. Specifically, in vitro studies using cultured podocytes indicate that exposure to Cd under hyperglycemic conditions leads to mitochondrial dysfunction and ROS.…”

“…Interestingly, exposure of these mice to Cd also decreased serum leptin levels, which may enhance appetite and lead to weight gain. In contrast to these findings, a recent study using streptozotocin-induced diabetic mice (C57BL/6) exposed to Cd showed that body weight decreased after exposure [ 138 ]. This variation could be due to differences in the frequency and dose of Cd exposure.…”

“…Specifically, in vitro studies using cultured podocytes indicate that exposure to Cd under hyperglycemic conditions leads to mitochondrial dysfunction and ROS. Podocyte viability is reduced, leading to apoptosis, fibrosis, and decreased renal function [ 138 ]. These studies suggest that exposure of diabetic individuals to Cd may exacerbate renal injury and lead to CKD or enhance the progression of CKD by causing additional injury.…”

A population-based urinary and plasma metabolomics study of environmental exposure to cadmium

“…In this study, we showed that leakage occurs to the extent that elevation of NAG does not occur, and there is the possibility that glomerular hyperfiltration and decrease of nephrons occur because of the decrease in plasma metabolites, creatinine and amino acids, and the broad elevation of urinary metabolites. Cd exposure has been suggested only for tubular disorders, but recent in vivo and in vitro studies have also focused on its effects on glomeruli at early, low concentrations exposure [ 63 , 64 ]. Thus, combined analysis of urinary and plasma metabolites could lead to better description of toxicological profiles of Cd in humans with deeper mechanistic understanding.…”

Protective effects of budesonide on LPS‑induced podocyte injury by modulating macrophage M1/M2 polarization: Evidence from in vitro and in silico studies

“…The CCK-8 assay has been used to determine the proliferation of podocyte cells, including the MPC-5 cell line ( 46 ) and human podocytes ( 47 ). BrdU is a nucleoside analog of thymidine and its incorporation into DNA during replication within S-phase of the cell cycle is used to quantify cell proliferation ( 48 ).…”