Hyperglycemia-Induced Changes in ZIP7 and ZnT7 Expression Cause Zn2+ Release From the Sarco(endo)plasmic Reticulum and Mediate ER Stress in the Heart

Abstract

Changes in cellular free Zn 2+ concentration, including those in the sarco(endo)plasmic reticulum [S(E)R], are primarily coordinated by Zn 2+-transporters whose identity and role in the heart is not well established. Here, we hypothesized that ZIP7 and ZnT7 transport Zn 2+ in opposing directions across the S(E)R membrane in cardiomyocytes and that changes in their activity may play an important role in the development of ER-stress during hyperglycemia.The subcellular S(E)R-localization of ZIP7 and ZnT7 was determined in cardiomyocytes and in isolated S(E)R-preparations. Markedly increased mRNA and protein levels of ZIP7 were observed in ventricular cardiomyocytes from diabetic rats or high glucose-treated H9c2 cells whilst ZnT7 expression was low. Additionally, we observed increased ZIP7-phosphorylation in response to high glucose in vivo and in vitro. Using recombinant targeted FRET-based sensors, we showed that hyperglycemia induced a marked redistribution of cellular free Zn 2+ , increasing cytosolic free Zn 2+ and lowering free Zn 2+ in the S(E)R. These changes involve alterations in ZIP7-phosphorylation and were suppressed by siRNA-mediated silencing of CK2α. Opposing changes in the expression of ZIP7 and ZnT7 were also observed in hyperglycemia. We conclude that sub-cellular free Zn 2+ re-distribution in the hyperglycemic heart, resulting from altered ZIP7 and ZnT7 activity, contributes to cardiac dysfunction in diabetes.

Protective Effect of Znt7 on High Glucose-Induced Epithelial-to-Mesenchymal Transition in Renal Tubular Epithelial Cells

“…The function of ZnT7 is to facilitate zinc transport from the cytoplasm into the Golgi apparatus and to regulate cellular zinc homeostasis [3]. In the present study, we used dual immunofluorescence of ZnT7 together with TGN38 and observed that ZnT7 was mainly located in the perinuclear region and Golgi apparatus of the NRK-52E cell, which is consistent with the reports from our [9, 10] and other groups [11, 26]. Furthermore, we found that ZnT7 facilitated Zn transport from the cytoplasm into the Golgi apparatus in the cells within 48 h of HG treatment.…”

“…A previous study showed that over-expression of ZnT7 in Chinese hamster ovarian cells under high zinc conditions lead to accumulation of free Zn 2+ in the Golgi apparatus [3]. A recent study demonstrated that hyperglycemia decreased ZnT7 activity following redistribution of cellular free Zn 2+ , which plays an important role during ER stress in cardiomyocytes [11]. In our present study, HG increased ZnT7 expression and over-expression of ZnT7 induced accumulation of free Zn 2+ in perinuclear region and Golgi apparatus of NRK-52E cells.…”

“…We further demonstrated that ZnT7 might inhibit HG-induced apoptosis by activation of the PI3K/Akt pathway [10]. Very recently, Tuncay et al provided evidence that ZnT7 up-regulation was observed in hyperglycemia, and alteration of ZnT7 activity could be involved in the pathogenesis of cardiac dysfunction in diabetes [11]. …”

Increased free Zn2+ correlates induction of sarco(endo)plasmic reticulum stress via altered expression levels of Zn2+‐transporters in heart failure

“…Indeed, we have previously shown that S(E)R function can be normalized when [Zn 2+ ] i is kept at normal level via enhancement of the antioxidant defence in diabetic rats . Recently, we have shown that Zn 2+ decrease in S(E)R leads to the up‐regulation of ER stress confirming the requirement of Zn 2+ for proper S(E)R function . However, there are no clear data on the role of Zn 2+ transporters controlling [Zn 2+ ] i in cardiomyocytes during the progression of HF, and, further studies are needed to clarify this important possible relation.…”

“…Furthermore, one isoform of PKC, PKCa, has been shown to have unique properties among other PKC isotypes in terms of induction of cardiac hypertrophy, and regulation of contractility and HF susceptibility [24][25][26]. Moreover, we recently have shown that hyperglycaemia induced marked changes in ZIP7 and ZnT7 expression levels underlined excess Zn 2+ release from S(E)R and could mediate ER stress in the heart [20].…”