TIAM1–RAC1 signalling axis-mediated activation of NADPH oxidase-2 initiates mitochondrial damage in the development of diabetic retinopathy

Kowluru, Renu A.; Kowluru, Anjaneyulu; Veluthakal, Rajakrishnan; Mohammad, Ghulam; Syed, Ismail; Santos, Júlia Matzenbacher dos; Mishra, Manish

doi:10.1007/s00125-014-3194-z

Cited by 121 publications

(206 citation statements)

References 46 publications

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“…Consistent with our data, a previous report showed that ROS production and Nox2 expression were increased in the diabetic retina [3,22,35]. Glycyrrhizin has been shown to bind HMGB1 and inhibit its cytokine-like activities [27].…”

Section: Discussionsupporting

confidence: 93%

“…In addition, we demonstrated that HMGB1 expression was upregulated in the retinas of diabetic mice and rats [1,26] and that HMGB1 plays a key role in mediating diabetes-induced retinal vasculopathy and neuropathy [22,1,26]. Five key findings emerged from this study.…”

Section: Discussionmentioning

confidence: 75%

“…NADPH oxidase-derived ROS generation is increased in the diabetic retina, causing retinal cells apoptosis which contributes to vasculopathy and neuropathy [3,22,35]. Extensive experimental data generated in both in vitro and in vivo models signify that diabetesinduced PARP-1 and caspase-3 overexpression in the retina causes cell death, a phenomenon that precedes the development of histopathologic changes [21,25,45].…”

Section: Discussionmentioning

confidence: 97%

“…More recent evidence suggests that the phagocytic Nox2 is the major endogenous intracellular source of superoxide production in vascular cells, leukocytes, and tissue macrophages. Its activation has been strongly implicated in the vascular complications of diabetes [12,14,22]. Previous studies documented that increased expression of Nox2 in the retina of diabetic mice and in retinal endothelial cells treated with high glucose was associated with upregulation of intracellular adhesion molecule-1 (ICAM-1) and vascular endothelial growth factor, increased leukocyte adhesion and breakdown of the blood-retinal barrier [3,35].…”

Section: Discussionmentioning

confidence: 98%

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Mutual enhancement between high-mobility group box-1 and NADPH oxidase-derived reactive oxygen species mediates diabetes-induced upregulation of retinal apoptotic markers

et al. 2015

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The expression of the proinflammatory cytokine high-mobility group box-1 (HMGB1) is upregulated in epiretinal membranes and vitreous fluid from patients with proliferative diabetic retinopathy (PDR) and in the diabetic retina. We hypothesized that a novel mechanism exists where HMGB1 and NADPH oxidase (Nox)-derived reactive oxygen species (ROS) are mutually enhanced in the diabetic retina, which may be a novel mechanism for promoting upregulation of retinal apoptotic markers induced by diabetes. Vitreous samples from 48 PDR and 34 nondiabetic patients, retinas from 1-month diabetic rats and from normal rats intravitreally injected with HMGB1 and human retinal microvascular endothelial cells (HRMEC) stimulated with HMGB1 were studied by enzyme-linked immunosorbent and spectrophotometric assays, Western blot analysis, RT-PCR, and immunofluorescence. We also studied the effect of the HMGB1 inhibitor glycyrrhizin and apocynin on diabetes-induced biochemical changes in the retinas of rats (n = 5-7 in each groups). HMGB1 and the oxidative stress marker protein carbonyl content levels in the vitreous fluid from PDR patients were significantly higher than in controls (p = 0.021; p = 0.005, respectively). There was a significant positive correlation between vitreous fluid levels of HMGB1 and the levels of protein carbonyl content (r = 0.62, p = 0.001). HMGB1 enhanced interleukin-1β, ROS, Nox2, poly (ADP-ribose) polymerase (PARP)-1, and cleaved caspase-3 production by HRMEC. Diabetes and intravitreal injection of HMGB1 in normal rats induced significant upregulation of ROS, Nox2, PARP-1, and cleaved caspase-3 in the retina. Constant glycyrrhizin and apocynin intake from onset of diabetes did not affect the metabolic status of the diabetic rats, but restored these increased mediators to control values. The results of this study suggest that there is a mutual enhancement between HMGB1 and Nox-derived ROS in the diabetic retina, which may promote diabetes-induced upregulation of retinal apoptotic markers.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 98%

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Mutual enhancement between high-mobility group box-1 and NADPH oxidase-derived reactive oxygen species mediates diabetes-induced upregulation of retinal apoptotic markers

et al. 2015

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“…94,96 In addition, recent studies from Sidarala and colleagues present the evidence that the Rac1-Nox2 signaling is vital in high glucose induced activation of stress activated kinases and loss in GSIS causing islet β-cell dysfunction. 97 Despite these in vitro evidences, potential roles for Nox in islet dysfunction in animal models of type 2 diabetes are minimal.…”

mentioning

confidence: 99%

Biphasic Roles of a Small G-Protein, RAC1 in Pancreatic Β-Cell

Parmar¹,

Meer²,

Syed³

2015

Gastro Open J

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Glucose-stimulated insulin secretion (GSIS) involves cross talk between small Gproteins and their regulating factors. These interactions results in translocation of insulin-laden granules to the plasma membrane for fusion and insulin release. Vesicular transport and fusion events are tightly regulated by signals which coordinate between vesicle-and membrane-associated docking proteins. It is now being accepted that small G-protein, Rac1-mediated Reactive Oxygen Species (ROS) functions as a second messenger in islet β-cell function. Further, evidence from multiple laboratories suggests a tonic increase in ROS generation is necessary for GSIS and fatty acid-induced insulin secretion. On the other hand, Rac1-mediated NADPH oxidase-activation and subsequent generation of excessive ROS under glucolipotoxic conditions and cytokines exposure has proven to be detrimental for islet β-cell function. In this review we overview the normal physiological effects (positive role) and adverse effects (negative role) of activated small G-protein, Rac1 in pancreatic β-cells.

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Molecular insights of NADPH oxidases and its pathological consequences

Waghela

Vaidya

Agrawal

et al. 2020

Cell Biochemistry & Function

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Reactive oxygen species (ROS), formed by the partial reduction of oxygen, were for a long time considered to be a byproduct of cellular metabolism. Since, increase in cellular levels of ROS results in oxidative stress leading to damage of nucleic acids, proteins, and lipids resulting in numerous pathological conditions; ROS was considered a bane for aerobic species. Hence, the discovery of NADPH oxidases (NOX), an enzyme family that specifically generates ROS as its prime product came as a surprise to redox biologists. NOX family proteins participate in various cellular functions including cell proliferation and differentiation, regulation of genes and protein expression, apoptosis, and host defence immunological response. Balanced expression and activation of NOX with subsequent production of ROS are critically important to regulate various genes and proteins to maintain homeostasis of the cell. However, dysregulation of NOX activation leading to enhanced ROS levels is associated with various pathophysiologies including diabetes, cardiovascular diseases, neurodegenerative diseases, ageing, atherosclerosis, and cancer. Although our current knowledge on NOX signifies its importance in the normal functioning of various cellular pathways; yet the choice of ROS producing enzymes which can tip the scale from homeostasis toward damage, as mediators of biological functions remain an oddity. Though the role of NOX in maintaining normal cellular functions is now deemed essential, yet its dysregulation leading to catastrophic events cannot be denied. Hence, this review focuses on the involvement of NOX enzymes in various pathological conditions imploring them as possible targets for therapies. Significance of the study The NOXs are multi‐subunit enzymes that generate ROS as a prime product. NOX generated ROS are usually regulated by various molecular factors and play a vital role in different physiological processes. The dysregulation of NOX activity is associated with pathological consequences. Recently, the dynamic proximity of NOX enzymes with different molecular signatures of pathologies has been studied extensively. It is essential to identify the precise role of NOX machinery in its niche during the progression of pathology. Although inhibition of NOX could be a promising approach for therapeutic interventions, it is critical to expand the current understanding of NOX's dynamicity and shed light on their molecular partners and regulators.

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TIAM1–RAC1 signalling axis-mediated activation of NADPH oxidase-2 initiates mitochondrial damage in the development of diabetic retinopathy

Cited by 121 publications

References 46 publications

Mutual enhancement between high-mobility group box-1 and NADPH oxidase-derived reactive oxygen species mediates diabetes-induced upregulation of retinal apoptotic markers

Mutual enhancement between high-mobility group box-1 and NADPH oxidase-derived reactive oxygen species mediates diabetes-induced upregulation of retinal apoptotic markers

Biphasic Roles of a Small G-Protein, RAC1 in Pancreatic Β-Cell

Molecular insights of NADPH oxidases and its pathological consequences

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