Hyperglycemia alters renal cell responsiveness to pressure in a model of malignant hypertension

Efrati, Shai; Berman, Sylvia; Tov, Yariv Siman; Averbukh, Zhan; Weissgarten, Joshua

doi:10.1097/hjh.0b013e32831b46ab

Cited by 9 publications

(23 citation statements)

References 39 publications

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“…The renal proximal tubular cell damage and apoptosis following the generation of ROS has been reported be responsible for the early stages of DN (3), and their sustained assault is believed to be critical in the progression of DN (34). The HG and ANG II seemed to be the key factors in the induction of intracellular ROS generation in the mitochondrial compartment, and that eventually leads to oxidative damage and apoptosis in renal cells (8,11,16,28). The p66Shc is a newly recognized mediator of mitochondrial dysfunction, which, by oxidizing Cyt.C in the mitochondria, leads to the generation of H 2 O 2 , and these sequence of events have been reported to be responsible for the pathogenesis of acute kidney injury in ischemia-reperfusion model (1).…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, an increased expression of both total and p-p66Shc protein expression was seen in the HK-2 cells treated with HG or ANG II. The HG has been shown to increase the synthesis of ANG II (8) and expression of p53, a transcription factor. Interestingly, the consensus sequences for the binding of this transcription factor have been localized in the promoter region of p66Shc (19).…”

Section: Discussionmentioning

confidence: 99%

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p66Shc mediates high-glucose and angiotensin II-induced oxidative stress renal tubular injury via mitochondrial-dependent apoptotic pathway

Sun

Xiao

Nie

et al. 2010

American Journal of Physiology-Renal Physiology

102

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

p66Shc mediates high-glucose and angiotensin II-induced oxidative stress renal tubular injury via mitochondrial-dependent apoptotic pathway

Sun

Xiao

Nie

et al. 2010

American Journal of Physiology-Renal Physiology

102

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“…Five randomly chosen non-malignant cell cultures, namely human peripheral blood mononuclear cells (PBMC), human umbilical cord endothelial cells (HUVEC), rat renal epithelial cell (EC) line, murine renal mesangial cells (MC) and renal embryonic cells (REC) isolated from metanephric mesenchymal tissues, served as normal controls. All cells were sub-cultured and maintained using their specific selective media [12,13]. After 3 to 5 passages, each cell population was seeded into the wells of 6 well-tissue culture plates, 2x10 6 cells per well, using their specific culture media supplemented with fetal calf serum (FCS).…”

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confidence: 99%

Low concentrations of Rhodamine-6G selectively destroy tumor cells and improve survival of melanoma transplanted mice

Kutushov

Gorelik²

2013

neo

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Rhodamine-6G is a fluorescent dye binding to mitochondria, thus reducing the intact mitochondria number and inhibiting mitochondrial metabolic activity. Resultantly, the respiratory chain functioning becomes blocked, the cell "suffocated" and eventually destroyed. Unlike normal cells, malignant cells demonstrate a priori reduced mitochondrial numbers and aberrant metabolism. Therefore, a turning point might exist, when Rhodamine-induced loss of active mitochondria would selectively destroy malignant, but spare normal cells. Various malignant vs. non-malignant cell lines were cultured with Rhodamine-6G at different concentrations. In addition, C57Bl mice were implanted with B16-F10 melanoma and treated with Rhodamine-6G at different dosage/time regimens. Viability and proliferation of cultured tumor cells were time and dose-dependently inhibited, up to 90%, by Rhodamine-6G, with profound histological signs of cell death. By contrast, inhibition of normal control cell proliferation hardly exceeded 15-17%. Melanoma-transplanted mice receiving Rhodamine-6G demonstrated prolonged survival, improved clinical parameters, inhibited tumor growth and metastases count, compared to their untreated counterparts. Twice-a-week 10 -6 M Rhodamine-6G regimen yielded the most prominent results. We conclude that malignant, but not normal, cells are selectively destroyed by low doses of Rhodamine-6G. In vivo, such treatment selectively suppresses tumor progression and dissemination, thus improving prognosis. We suggest that selective anti-tumor properties of Rhodamine-6G are based on unique physiologic differences in energy metabolism between malignant and normal cells. If found clinically relevant, low concentrations of Rhodamine-6G might be useful for replacing, or backing up, more aggressive nonselective chemotherapeutic compounds. Key words: warburg effect, tumor, cell culture, melanoma, rhodamine-6G, mitochondriaCancer cells are unique in their energy turnover. Unlike normal tissues that derive most of their energy by metabolizing the consumed sugar to carbon dioxide and water (the process taking place within mitochondria), tumors obtain as much as half of their ATP by metabolizing glucose directly to lactic acid. Normal tissues use the process of oxidative phosphorylation within mitochondria for 90% of ATP production, and only 10% is produced by glucose consumption. By contrast, in tumor cells this ratio is 50%:50% [1][2][3]. This unique pattern of tumor metabolism has been described in early thirties of the past century and has been recognized since then as Warburg effect [1][2][3]. Recent studies employing molecular biology and proteomic imaging technologies, explained the basics of Warburg effect [4,5].Rhodamine-6G is a fluorescent dye capable of penetrating a living cell [6]. Upon entering the cell, Rhodamine-6G binds to the inner membranes of mitochondria. Based on these observations, it has been proposed that Rhodamine dyes may be used for producing fluorescent images of mitochondria with low background noise and high re...

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“…Using an in vitro model of pressure-induced malignant hypertension, we have previously shown that mesangial cells play a deleterious role in orchestrating the acute renal tissue insult that is associated with malignant hypertension [1, 24, 25]. In this study, we focused on the podocytes.…”

Section: Discussionmentioning

confidence: 99%

“…The in-vitro model of malignant hypertension has allowed the investigation of paracrine crosstalk among various renal cell populations and their role in RAS activation in pressure-induced renal injury [1, 24, 25]. The first studies were performed on podocytes and mesangial cells firmly attached to culture vessels.…”

Section: Introductionmentioning

confidence: 99%

Response of Renal Podocytes to Excessive Hydrostatic Pressure: a Pathophysiologic Cascade in a Malignant Hypertension Model

Hamad¹,

Berman²,

Hachmo³

et al. 2017

Kidney Blood Press Res

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Background/Aims: Renal injuries induced by increased intra-glomerular pressure coincide with podocyte detachment from the glomerular basement membrane (GBM). In previous studies, it was demonstrated that mesangial cells have a crucial role in the pathogenesis of malignant hypertension. However, the exact pathophysiological cascade responsible for podocyte detachment and its relationship with mesangial cells has not been fully elucidated yet and this was the aim of the current study. Methods: Rat renal mesangial or podocytes were exposed to high hydrostatic pressure in an in-vitro model of malignant hypertension. The resulted effects on podocyte detachment, apoptosis and expression of podocin and integrinβ₁ in addition to Angiotensin-II and TGF-β1 generation were evaluated. To simulate the paracrine effect podocytes were placed in mesangial cell media pre-exposed to pressure, or in media enriched with Angiotensin-II, TGF-β1 or receptor blockers. Results: High pressure resulted in increased Angiotensin-II levels in mesangial and podocyte cells. Angiotensin-II via the AT1 receptors reduced podocin expression and integrinβ₁, culminating in detachment of both viable and apoptotic podocytes. Mesangial cells exposed to pressure had a greater increase in Angiotensin-II than pressure-exposed podocytes. The massively increased concentration of Angiotensin-II by mesangial cells, together with increased TGF-β1 production, resulted in increased apoptosis and detachment of non-viable apoptotic podocytes. Unlike the direct effect of pressure on podocytes, the mesangial mediated effects were not related to changes in adhesion proteins expression. Conclusions: Hypertension induces podocyte detachment by autocrine and paracrine effects. In a direct response to pressure, podocytes increase Angiotensin-II levels. This leads, via AT1 receptors, to structural changes in adhesion proteins, culminating in viable podocyte detachment. Paracrine effects of hypertension, mediated by mesangial cells, lead to higher levels of both Angiotensin-II and TGF-β1, culminating in apoptosis and detachment of non-viable podocytes.

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Hyperglycemia alters renal cell responsiveness to pressure in a model of malignant hypertension

Cited by 9 publications

References 39 publications

p66Shc mediates high-glucose and angiotensin II-induced oxidative stress renal tubular injury via mitochondrial-dependent apoptotic pathway

p66Shc mediates high-glucose and angiotensin II-induced oxidative stress renal tubular injury via mitochondrial-dependent apoptotic pathway

Low concentrations of Rhodamine-6G selectively destroy tumor cells and improve survival of melanoma transplanted mice

Response of Renal Podocytes to Excessive Hydrostatic Pressure: a Pathophysiologic Cascade in a Malignant Hypertension Model

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