Mitochondrial stress and activation of PI3K and Akt survival pathway in bladder ischemia

Yang, Jinghua; Siroky, Mike B.; Yalla, Subbarao V.; Azadzoi, Kazem M.

doi:10.2147/rru.s132082

Cited by 22 publications

(59 citation statements)

References 34 publications

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“…Is supported from the following observations: Firstly, G-CSF treatment showed significant inhibition of apoptosis by activation of the PERK, ATF6 and IRE-1 pathways. We showed upregulation of Akt phosphorylation which can inhibit ischemia-induced apoptosis [59], attenuate ER stress [60] and lessen mitochondrial stress [61]. Secondly, administration of G-CSF showed that an increase in Beclin 1, LC3 I & II, CHOP and Bax was prevented in the frontal and middle brain of BCAO stroke model indicating that G-CSF can decrease autophagy (down regulation of Beclin 1) and apoptosis both in mitochondrial Ca2 + −induced apoptosis (up-regulation of BCL-2/Bax and down-regulation of Bak) and ER-induced apoptosis (down-regulation of CHOP).…”

Section: Resultsmentioning

confidence: 85%

Mode of action of granulocyte-colony stimulating factor (G-CSF) as a novel therapy for stroke in a mouse model

Modi

Menzie-Suderam

et al. 2020

J Biomed Sci

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Background: The FDA approved drug granulocyte-colony stimulating factor (G-CSF) displays anti-apoptotic and immunomodulatory properties with neurogenesis and angiogenic functions. It is known to demonstrate neuroprotective mechanisms against ischemic global stroke. Autophagy is a method for the degradation of intracellular components and in particular, unrestrained autophagy may lead to uncontrolled digestion of affected neurons as well as neuronal death in cerebral ischemia. Mitochondrial dynamics is vital for the regulation of cell survival and death after cerebral ischemia and an early upstream event in neuronal death is mitochondrial fission. We examined the pro-survival mechanisms of G-CSF against apoptosis resulting from autophagy, mitochondrial stress and endoplasmic reticulum (ER) stress. Methods: Male Swiss Webster mice (20 weeks of age) were subjected to bilateral common carotid artery occlusion (BCAO) for 30 min. After occlusion, mice were injected with G-CSF (50 μg/kg) subcutaneously for 4 days. Behavioral analysis was carried out using the corner test and locomotor activity test before animals were sacrificed on day 4 or day 7. Key proteins in ER stress, autophagy and mitochondrial stress induced apoptosis were analyzed by immunoblotting.Results: G-CSF improved neurological deficits and improved behavioral performance on corner and locomotor test. G-CSF binds to G-CSF receptors and its activation leads to upregulation of Akt phosphorylation (P-Akt) which in turn decreases levels of the ER stress sensor, GRP 78 and expression of proteins involved in ER stress apoptosis pathway; ATF6, ATF4, eIF2α, XBP1, Caspase 12 and CHOP. G-CSF treatment significantly decreased Beclin-1, an autophagy marker, and decreased mitochondrial stress biomarkers DRP1 and P53. G-CSF also up-regulated the mitochondrial fusion protein, OPA1 and anti-apoptotic protein Bcl-2 while down-regulating the pro-apoptotic proteins Bax, Bak and PUMA. Conclusions: G-CSF is an endogenous ligand in the CNS that has a dual activity that is beneficial both in reducing acute neuronal degeneration and adding to long-term plasticity after cerebral ischemia. G-CSF treatment exerts neuroprotective effects on damaged neurons through the suppression of the ER stress and mitochondrial stress and maintains cellular homeostasis by decreasing pro-apoptotic proteins and increasing of anti-apoptotic proteins.

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Section: Resultsmentioning

confidence: 85%

Mode of action of granulocyte-colony stimulating factor (G-CSF) as a novel therapy for stroke in a mouse model

Modi

Menzie-Suderam

et al. 2020

J Biomed Sci

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“…9 These changes in the ischemic bladder were associated with impairment of cellular antioxidant defense system, mitochondrial structural damage, depression of mitochondrial respiration and activation of cell survival signaling. 10 Hypoxia, nutrients deficiency, and accumulation of metabolic waste in bladder ischemia were shown to compromise cellular homeostasis and initiate defensive responses via rebalancing mechanisms to protect cells against the ischemic insult. 6 – 10 However, when ischemia persists, noxious free radicals prevail and cellular protective mechanisms decline leading to activation of cell danger responses and cellular stress signaling.…”

Section: Introductionmentioning

confidence: 99%

“… 10 Hypoxia, nutrients deficiency, and accumulation of metabolic waste in bladder ischemia were shown to compromise cellular homeostasis and initiate defensive responses via rebalancing mechanisms to protect cells against the ischemic insult. 6 – 10 However, when ischemia persists, noxious free radicals prevail and cellular protective mechanisms decline leading to activation of cell danger responses and cellular stress signaling. 6 – 10 …”

Section: Introductionmentioning

confidence: 99%

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<p>Regulation of Cellular Stress Signaling in Bladder Ischemia</p>

Yang¹,

Li²,

Azad³

et al. 2020

RRU

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Introduction The etiology of lower urinary tract symptoms in patients with non-obstructed non-neurogenic bladder remains largely unknown. Clinical studies divulged a significant correlation between reduced bladder blood flow and low bladder compliance. Animal models of bladder ischemia displayed structural modifications, characterized by loss of smooth muscle cells and accumulation of connective tissue in the bladder wall. The underlying mechanisms contributing to structural damage in bladder ischemia remain largely elusive. We previously reported that structural modifications in bladder ischemia correlate with upregulated stress proteins and cell survival signaling, suggesting the potential role of cellular stress in ischemic damage. However, stress response molecules and downstream pathways eliciting bladder damage in ischemia remain largely undetermined. Methods Using a rat model of bladder ischemia along with a cell culture hypoxia model, we investigated stress signaling molecules in the ischemic bladder tissues and hypoxic bladder smooth muscle cells. Results Our data suggest simultaneous upregulation of two major cellular stress-sensing molecules, namely apoptosis signal-regulating kinase 1 (ASK1) and caspase-3, implying degenerative insult via stress signaling pathway in bladder ischemia. Consistent with bladder ischemia, incubation of cultured human bladder smooth muscle cells at low oxygen tension increased both ASK1 and caspase-3 expression, insinuating hypoxia as an essential factor in ASK1 and caspase-3 upregulation. Gene deletion of ASK1 by ASK1 siRNA in cultured smooth muscle cells prevented caspase-3 upregulation by hypoxia, suggesting caspase-3 regulation by ASK1 under the ischemic/hypoxic conditions. Upregulation of ASK1 and caspase-3 in rat bladder ischemia and human bladder smooth muscle cell hypoxia was associated with subcellular structural modifications consistent with the initial stages of apoptotic insult. Conclusion Our data suggest that stress sensing by ASK1 and caspase-3 may contribute to subcellular structural damage and low bladder compliance. The ASK1/caspase-3 pathway may provide therapeutic targets against cellular stress and degenerative responses in bladder ischemia.

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“…Under these conditions, DMH-1 could actually activate AMPK indirectly, because AMPK activation is usually a consequence of a decrease in ATP production. Besides, a relationship between AKT activation and mitochondrial stress has also been reported (Bijur and Jope, 2003;Guha et al, 2010;Yang et al, 2017).…”

Section: Nutrient-sensitive Pathways Modulators and C Elegans Longevitymentioning

confidence: 83%

Effects of AMP-activated kinase modulators on intracellular Ca2+ signalling and C. elegans lifespan

Val¹

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Mitochondrial stress and activation of PI3K and Akt survival pathway in bladder ischemia

Cited by 22 publications

References 34 publications

Mode of action of granulocyte-colony stimulating factor (G-CSF) as a novel therapy for stroke in a mouse model

Mode of action of granulocyte-colony stimulating factor (G-CSF) as a novel therapy for stroke in a mouse model

<p>Regulation of Cellular Stress Signaling in Bladder Ischemia</p>

Effects of AMP-activated kinase modulators on intracellular Ca2+ signalling and C. elegans lifespan

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