Hyperglycemia Does Not Affect Iron Mediated Toxicity of Cultured Endothelial and Renal Tubular Epithelial Cells: Influence of L-Carnosine.

Shiqi Zhang,Stephan J L Bakker,Bernhard K Krämer,Jaap Van Den Born,Gerjan Navis,Benito A Yard,Emmanouil Ntasis,Sibylle J Hauske,Sarah Kabtni

doi:10.1155/2016/8710432

Abstract

Iron has been suggested to affect the clinical course of type 2 diabetes (T2DM) as accompanying increased intracellular iron accumulation may provide an alternative source for reactive oxygen species (ROS). Although carnosine has proven its therapeutic efficacy in rodent models of T2DM, little is known about its efficacy to protect cells from iron toxicity. We sought to assess if high glucose (HG) exposure makes cultured human umbilical vein endothelial cells (HUVECs) and renal proximal tubular epithelial cells (PTECs) more susceptible to metal induced toxicity and if this is ameliorated by L-carnosine. HUVECs and PTECs, cultured under normal glucose (5 mM, NG) or HG (30 mM), were challenged for 24 h with FeCl3. Cell viability was not impaired under HG conditions nor did HG increase susceptibility to FeCl3. HG did not change the expression of divalent metal transporter 1 (DMT1), ferroportin (IREG), and transferrin receptor protein 1 (TFRC). Irrespective of glucose concentrations L-carnosine prevented toxicity in a dose-dependent manner, only if it was present during the FeCl3 challenge. Hence our study indicates that iron induced cytotoxicity is not enhanced under HG conditions. L-Carnosine displayed a strong protective effect, most likely by chelation of iron mediated toxicity.

Highlights

High body iron levels are associated with increased levels of oxidative stress that may elevate the risk of T2DM [1,2,3,4,5,6,7]
To assess susceptibility of human umbilical vein endothelial cells (HUVECs) and proximal tubular epithelial cells (PTECs) to transition metal mediated toxicity cells were challenged for 24 h with different concentrations of FeCl3 or ZnCl2
Since HUVECs medium contains 2% fetal calf serum (FCS) while PTECs are cultured in serum-free culture medium supplemented with transferrin, we tested if this might explain the difference in susceptibility between HUVECs and PTECs

Summary

Introduction

High body iron levels are associated with increased levels of oxidative stress that may elevate the risk of T2DM [1,2,3,4,5,6,7]. Epidemiological studies have indicated a positive association between high body iron stores and the risk of T2DM and of other insulin resistant states such as metabolic syndrome, gestational diabetes, and polycystic ovarian syndrome [8,9,10,11]. High ferritin levels in T2DM are closely related to the development of diabetic vascular complications, possibly through the interaction with vascular endothelial growth factor (VEGF) [12] or through endothelial dysfunction [13]. Studies performed in the Belgrade rat, which carries a mutation in the iron transporter DMT1, demonstrate that these rats displayed normal glycemic control and insulin signaling and secretion despite high levels of nonheme iron [15]

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Conclusion