Insulin-Like Growth Factor-Binding Protein-3 Mediates High Glucose-Induced Apoptosis by Increasing Oxidative Stress in Proximal Tubular Epithelial Cells

Metallothionein (MT) is an intracellular metal-binding, cysteine-rich protein, and is a potent antioxidant that protects cells and tissues from oxidative stress. Although the major isoforms MT-1 and -2 (MT-1/-2) are highly inducible in many tissues, the distribution and role of MT-1/-2 in diabetic nephropathy are poorly understood. In this study, diabetes was induced in adult male rats by streptozotocin, and renal tissues were stained with antibodies for MT-1/-2. MT-1/-2 expression was also evaluated in mProx24 cells, a mouse renal proximal tubular epithelial cell line, stimulated with high glucose medium and pretreated with the antioxidant vitamin E. MT-1/-2 expression was gradually and dramatically increased, mainly in the proximal tubular epithelial cells and to a lesser extent in the podocytes in diabetic rats, but was hardly observed in control rats. MT-1/-2 expression was also increased by high glucose stimulation in mProx24 cells. Because the induction of MT was suppressed by pretreatment with vitamin E, the expression of MT-1/-2 is induced, at least in part, by high glucose-induced oxidative stress. These observations suggest that MT-1/-2 is induced in renal proximal tubular epithelial cells as an antioxidant to protect the kidney from oxidative stress, and may offer a novel therapeutic target against diabetic nephropathy.

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Metallothionein deficiency exacerbates diabetic nephropathy in streptozotocin-induced diabetic mice

AJP Renal Physiology ◽

10.1152/ajprenal.00034.2013 ◽

2014 ◽

Vol 306 (1) ◽

pp. F105-F115 ◽

Cited By ~ 13

Author(s):

Hiromi Tachibana ◽

Daisuke Ogawa ◽

Norio Sogawa ◽

Masato Asanuma ◽

Ikuko Miyazaki ◽

...

Keyword(s):

Oxidative Stress ◽

Diabetic Nephropathy ◽

Epithelial Cells ◽

High Glucose ◽

Tubular Epithelial Cells ◽

Diabetic Kidney ◽

Proximal Tubular Epithelial Cells ◽

Proximal Tubular ◽

In The Diabetic Kidney

Oxidative stress and inflammation play important roles in diabetic complications, including diabetic nephropathy. Metallothionein (MT) is induced in proximal tubular epithelial cells as an antioxidant in the diabetic kidney; however, the role of MT in renal function remains unclear. We therefore investigated whether MT deficiency accelerates diabetic nephropathy through oxidative stress and inflammation. Diabetes was induced by streptozotocin injection in MT-deficient (MT−/−) and MT+/+ mice. Urinary albumin excretion, histological changes, markers for reactive oxygen species (ROS), and kidney inflammation were measured. Murine proximal tubular epithelial (mProx24) cells were used to further elucidate the role of MT under high-glucose conditions. Parameters of diabetic nephropathy and markers of ROS and inflammation were accelerated in diabetic MT−/− mice compared with diabetic MT+/+ mice, despite equivalent levels of hyperglycemia. MT deficiency accelerated interstitial fibrosis and macrophage infiltration into the interstitium in the diabetic kidney. Electron microscopy revealed abnormal mitochondrial morphology in proximal tubular epithelial cells in diabetic MT−/− mice. In vitro studies demonstrated that knockdown of MT by small interfering RNA enhanced mitochondrial ROS generation and inflammation-related gene expression in mProx24 cells cultured under high-glucose conditions. The results of this study suggest that MT may play a key role in protecting the kidney against high glucose-induced ROS and subsequent inflammation in diabetic nephropathy.

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Protection against Oxidative Stress, Inflammation, and Apoptosis of High-Glucose-Exposed Proximal Tubular Epithelial Cells by Astaxanthin

Journal of Agricultural and Food Chemistry ◽

10.1021/jf9019745 ◽

2009 ◽

Vol 57 (19) ◽

pp. 8793-8797 ◽

Cited By ~ 55

Author(s):

You Jung Kim ◽

Young Ae Kim ◽

Takako Yokozawa

Keyword(s):

Oxidative Stress ◽

Epithelial Cells ◽

High Glucose ◽

Tubular Epithelial Cells ◽

Proximal Tubular Epithelial Cells ◽

Proximal Tubular

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Pyridoxamine Treatment of HK-2 Human Proximal Tubular Epithelial Cells Reduces Oxidative Stress and the Inhibition of Autophagy Induced by High Glucose Levels

Medical Science Monitor ◽

10.12659/msm.914799 ◽

2019 ◽

Vol 25 ◽

pp. 1480-1488 ◽

Cited By ~ 4

Author(s):

Ying Wang ◽

Ying Li ◽

Zhiping Yang ◽

Ziqiang Wang ◽

Jiang Chang ◽

...

Keyword(s):

Oxidative Stress ◽

Epithelial Cells ◽

High Glucose ◽

Tubular Epithelial Cells ◽

Glucose Levels ◽

Proximal Tubular Epithelial Cells ◽

Proximal Tubular

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LincRNA-p21 Inhibits Cisplatin-Induced Apoptosis of Human Renal Proximal Tubular Epithelial Cells by Sponging miR-449a

Kidney & Blood Pressure Research ◽

10.1159/000509229 ◽

2021 ◽

pp. 1-7

Author(s):

Zhen Li ◽

Gang Hou

Keyword(s):

Breast Cancer ◽

Epithelial Cells ◽

Kidney Injury ◽

Protective Role ◽

Tubular Epithelial Cells ◽

Breast Cancer Patients ◽

Proximal Tubular Epithelial Cells ◽

Proximal Tubular ◽

Renal Proximal Tubular ◽

Induced Apoptosis

Introduction: LincRNA-p21 is predicted to interact with miR-449a, which plays a protective role in cisplatin-induced acute kidney injury (CIA). Objective: This study aimed to analyze the involvement of lincRNA-p21 in breast cancer patients with CIA. Methods: Levels of lincRNA-p21 in plasma from CIA, triple negative breast cancer, and control groups were measured by performing RT-qPCR. The potential interaction between lincRNA-p21 and miR-449a was first predicted by RT-qPCR. The relationship between lincRNA-p21 and miR-449a was analyzed by overexpression experiment. Results: We found that lincRNA-p21 is downregulated in CIA. Dual luciferase activity assay showed that lincRNA-p21 and miR-449a can interact with each other, while overexpression of lincRNA-p21 and miR-449a failed to affect the expression of each other. In human renal proximal tubular epithelial cells (HRPTEpCs), cisplatin led to the upregulated miR-449a but downregulated lincRNA-p21. Interestingly, lincRNA-p21 overexpression led to reduced enhancing effects of miR-449a on the cisplatin-induced apoptosis of HRPTEpCs. Conclusion: Therefore, lincRNA-p21 is downregulated in CIA and may sponge miR-449a to inhibit cisplatin-induced apoptosis of HRPTEpCs.

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TCR+CD4−CD8− (double negative) T cells protect from cisplatin-induced renal epithelial cell apoptosis and acute kidney injury

AJP Renal Physiology ◽

10.1152/ajprenal.00033.2020 ◽

2020 ◽

Vol 318 (6) ◽

pp. F1500-F1512

Author(s):

Jing Gong ◽

Sanjeev Noel ◽

Joshua Hsu ◽

Errol L. Bush ◽

Lois J. Arend ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Epithelial Cells ◽

Kidney Injury ◽

Double Negative ◽

Tubular Epithelial Cells ◽

Proximal Tubular Epithelial Cells ◽

Proximal Tubular ◽

Induced Apoptosis

Acute kidney injury (AKI) due to cisplatin is a significant problem that limits its use as an effective chemotherapeutic agent. T cell receptor+CD4−CD8− double negative (DN) T cells constitute the major T cell population in the human and mouse kidney, express programmed cell death protein (PD)-1, and protect from ischemic AKI. However, the pathophysiological roles of DN T cells in cisplatin-induced AKI is unknown. In this study, wild-type mice were treated with cisplatin (30 mg/kg) or vehicle, and the effects on kidney DN T cell numbers and function were measured. In vitro experiments evaluated effects of kidney DN T cells on cisplatin-induced apoptosis and PD ligand 1 (PD-L1) in renal epithelial cells. Adoptive transfer experiments assessed the therapeutic potential of DN T cells during cisplatin-induced AKI. Our results show that kidney DN T cell population increased at 24 h and declined by 72 h after cisplatin treatment. Cisplatin treatment increased kidney DN T cell proliferation, apoptosis, CD69, and IL-10 expression, whereas CD62L, CD44, IL-17A, interferon-γ, and TNF-α were downregulated. Cisplatin treatment decreased both PD-1 and natural killer 1.1 subsets of kidney DN T cells with a pronounced effect on the PD-1 subset. In vitro kidney DN T cell coculture decreased cisplatin-induced apoptosis in kidney proximal tubular epithelial cells, increased Bcl-2, and decreased cleaved caspase 3 expression. Cisplatin-induced expression of PD ligand 1 was reduced in proximal tubular epithelial cells cocultured with DN T cells. Adoptive transfer of DN T cells attenuated kidney dysfunction and structural damage from cisplatin-induced AKI. These results demonstrate that kidney DN T cells respond rapidly and play a protective role during cisplatin-induced AKI.

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