Metallothionein deletion exacerbates intermittent hypoxia-induced renal injury in mice

Wu, Hao; Zhou, Shanshan; Kong, Lili; Chen, Jing; Feng, Wenke; Cai, Jun; Miao, Lining; Tan, Yi

doi:10.1016/j.toxlet.2014.11.015

Cited by 55 publications

(57 citation statements)

References 59 publications

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“…In experimental settings, MTT induction in the kidney protects the tissues from oxidative stress [19]. In hypoxia, MTTs may play an important protective role: Wu et al [29] demonstrated in a mouse model that depletion of MTTs worsened hypoxia-induced renal injury, and an increase in MTT-expression stabilizes hypoxia-inducible factor in the kidney [10]. Moreover, kidneys were less susceptible for hypoxia-induced apoptosis in a setting of overexpression of MT2A [18].…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, previous studies have shown no MTT increase under chronic hypoxic conditions and during development of chronic kidney disease. Wu et al [29] demonstrated that during intermittent hypoxia for > 8 weeks accompanied by renal fibrosis, no increase in MTTs was detectable, whereas initially an increased expression of MTTs occurred. Sun et al [37] also showed that short-term oxidative stress (during hypoxia) induced MTTs, whereas long-term hypoxia did not affect MTTs.…”

Section: Discussionmentioning

confidence: 99%

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Renal effects of metallothionein induction by zinc in vitro and in vivo

et al. 2017

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BackgroundMetallothionein (MTT) is an endogenous antioxidant that can be induced by both zinc (Zn) and ischemia. In kidneys, increased MTT expression exerts a putative protective role in diabetes and hypoxia. Our goal was to further investigate the behavior of MTT under the influence of Zn and hypoxia in vitro and in vivo.MethodsMTT expression was measured in vitro in cell cultures of proximal tubular cells (LCC-PK1) by immune-histochemistry and real-time PCR after incubation with increasing concentrations of Zn under hypoxic and non-hypoxic conditions. In addition, in vivo studies were carried out in 54 patients to study MTT induction through Zn. This is a sub-study of a prospective, randomized, double-blind trial on prevention of contrast-media-induced nephropathy using Placebo, Zn and N-Acetylcysteine. Blood samples were obtained before and after 2 days p.o. treatment with or without Zn (60 mg). ELISA-based MTT level measurements were done to evaluate the effects of Zn administration. For in vivo analysis, we considered the ratio of MTT to baseline MTT (MTT1/MTT0) and the ratio of eGFR (eGFR1/eGFR0), correspondingly.Results In vitro quantitative immuno-histochemical analysis (IHC) and real-time PCR showed that at increasing levels of Zn (5, 10, and 15 μg/ml) led to a progressive increase of MTTs: Median (IQR) expression of IHC also increased progressively from 0.10 (0.09–0.12), 0.15 (0.12–0.18), 0.25 (0.25–0.27), 0.59 (0.48–0.70) (p < 0.0001). Median (IQR) expression of PCR: 0.59 (0.51–1.72), 1.62 (1.38–4.70), 3.58 (3.06–10.42) and 10.81 (9.24–31.47) (p < 0.0001). In contrast, hypoxia did not change MTT-levels in vitro (p > 0.05). In vivo no significant differences (p = 0.96) occurred in MTT-levels after 2 days of Zn administration compared with no Zn intake. Nevertheless, there was a significant correlation between MTT (MTT1/MTT0) and eGFR (eGFR1/eGFR0) in case of Zn administration (rho = −0.49; 95%-CI: −0.78 to −0.03; p = 0.04).ConclusionsWe found that Zn did induce MTTs in vitro, whereas hypoxia had no significant impact. In contrast, no significant increase of MTTs was detected after in vivo administration of Zn. However, there was a significant negative correlation between MTT and eGFR in vivo in case of Zn administration, this could indicate a protective role of MTTs in a setting of reduced kidney function, which is possibly influenced by Zn.Trial registrationClinicalTrials.gov Identifier: NCT00399256. Retrospectively registered 11/13/2006.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Renal effects of metallothionein induction by zinc in vitro and in vivo

et al. 2017

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“…However, MTs conversely protect against cardiomyopathy, renal injury, and burn sepsis, through Akt activation as survival signaling. [43–45] The complicated functions of MTs may depend on their expression levels, cell type, and the intracellular environment, including metal ion concentration and redox valence. In addition, because it seems that MTs siRNA affected Mt2 expression for only 1–2 days after transfection in this study (Fig 2B), the contribution of MTs siRNA could be evaluated for only the initial stage of the differentiation of 3T3-L1 cells, and not for later stages.…”

Section: Discussionmentioning

confidence: 99%

Metallothioneins regulate the adipogenic differentiation of 3T3-L1 cells via the insulin signaling pathway

et al. 2017

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Knockout of metallothionein (MT) genes contributes to a heavier body weight in early life and the potential to become obese through the intake of a high fat diet (HFD) in mice. It has thus been suggested that MT genes regulate the formation of adipose tissue, which would become the base for later HFD-induced obesity. We evaluated the fat pads of mice during the lactation stage. The fat mass and adipocyte size of MT1 and MT2 knockout mice were greater than those of wild type mice. Next, we assayed the ability of small interfering RNA (siRNA) to silence MT genes in the 3T3-L1 cell line. The expressions of MT1 and MT2 genes were transiently upregulated during adipocyte differentiation, and the siRNA pretreatment led to the suppression of the expression of both MT mRNAs and proteins. The MT siRNA promoted lipid accumulation in adipocytes and caused proliferation of post-confluent preadipocytes; these effects were suppressed by an inhibitor of phosphatidylinositol 3-kinase (LY294002). In addition, MT siRNA promoted insulin-stimulated phosphorylation of Akt, a downstream kinase of the insulin signaling pathway. Enhanced lipid accumulation in 3T3-L1 cells resulting from MT-gene silencing was inhibited by pretreatment with an antioxidant, N-acetylcysteine, used as a substitute for antioxidant protein MTs. These results suggest that interference in MT expression enhanced the activation of the insulin signaling pathway, resulting in higher lipid accumulation in 3T3-L1 adipocytes.

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“…Quantitative RT-PCR (qRT-PCR) was performed as described in our previous studies [26, 27]. qRT-PCR for miRNAs was performed with the TaqMan MicroRNA Reverse Transcription Kit (Life Technologies, Grand Island, NY, USA).…”

Section: Quantitative Reverse Transcription Pcrmentioning

confidence: 99%

C66 ameliorates diabetic nephropathy in mice by both upregulating NRF2 function via increase in miR-200a and inhibiting miR-21

Kong

Tan

et al. 2016

Diabetologia

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Aims/hypothesis Diabetic nephropathy is the leading cause of end-stage renal disease. Previously we reported that C66, a novel analogue of curcumin with a very high bioavailability, ameliorated diabetic nephropathy in mice, with little known about the mechanism. The present study aimed to define the mechanism by which C66 ameliorates diabetic nephropathy. Methods Our aim was to discover whether C66 acts through the activation of nuclear factor (erythroid-derived 2)-like 2 (NFE2L2 or NRF2), which governs the antioxidant response. Streptozotocin-induced Nrf2 (also known as Nfe2l2)-knockout and wild-type (WT) diabetic mice were treated with C66. To determine whether the actions of C66 on NRF2 are mediated by microRNA (miR)-200a, WT diabetic mice were treated with C66 in the presence or absence of an in vivo miR-200a inhibitor (locked nucleic acid-modified anti-miR-200a [LNA-200a]) for 6 months. To determine whether miR-21 downregulation provided an NRF2-independent basis for C66 protection, Nrf2-knockout diabetic mice were treated with either C66 or an inhibitor of miR-21 (locked nucleic acid-modified anti-miR-21 [LNA-21]). Results Deletion of Nrf2 partially abolished diabetic nephropathy protection by C66, confirming the requirement of NRF2 for this protection. Diabetic mice, but not C66-treated diabetic mice, developed significant albuminuria, renal oxidative damage and fibrosis. C66 upregulated renal miR-200a, inhibited kelch-like ECH-associated protein 1 and induced NRF2 function, effects that were prevented by LNA-200a. However, LNA-200a only partially reduced the protection afforded by C66, suggesting the existence of miR-200a/NRF2-independent mechanisms for C66 protection. C66 was also found to inhibit diabetes induction of miR-21. Both C66 and LNA-21 produced similar reductions in miR-21, albuminuria and renal fibrosis. Conclusions/interpretation The present study indicates that in addition to upregulating NRF2 by increasing miR-200a, C66 also protects against diabetic nephropathy by inhibiting miR-21.

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Metallothionein deletion exacerbates intermittent hypoxia-induced renal injury in mice

Cited by 55 publications

References 59 publications

Renal effects of metallothionein induction by zinc in vitro and in vivo

Renal effects of metallothionein induction by zinc in vitro and in vivo

Metallothioneins regulate the adipogenic differentiation of 3T3-L1 cells via the insulin signaling pathway

C66 ameliorates diabetic nephropathy in mice by both upregulating NRF2 function via increase in miR-200a and inhibiting miR-21

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