High glucose-induced RhoA activation requires caveolae and PKCβ1-mediated ROS generation

Zhang, Yong; Peng, Fei; Gao, Bo; Ingram, Alistair J.; Krepinsky, Joan C.

doi:10.1152/ajprenal.00749.2010

Cited by 30 publications

(28 citation statements)

References 62 publications

(102 reference statements)

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“…Given that PKCβ 1 activation induced by HG requires caveolae in primary mesangial cells (32), we determined whether caveolae are crucial in HG-induced PKCβ 2 activation in isolated cardiomyocytes from nondiabetic rats. As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Hyperglycemia-Induced Protein Kinase C β2 Activation Induces Diastolic Cardiac Dysfunction in Diabetic Rats by Impairing Caveolin-3 Expression and Akt/eNOS Signaling

et al. 2013

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Protein kinase C (PKC)β2 is preferably overexpressed in the diabetic myocardium, which induces cardiomyocyte hypertrophy and contributes to diabetic cardiomyopathy, but the underlying mechanisms are incompletely understood. Caveolae are critical in signal transduction of PKC isoforms in cardiomyocytes. Caveolin (Cav)-3, the cardiomyocyte-specific caveolar structural protein isoform, is decreased in the diabetic heart. The current study determined whether PKCβ2 activation affects caveolae and Cav-3 expression. Immunoprecipitation and immunofluorescence analysis revealed that high glucose (HG) increased the association and colocalization of PKCβ2 and Cav-3 in isolated cardiomyocytes. Disruption of caveolae by methyl-β-cyclodextrin or Cav-3 small interfering (si)RNA transfection prevented HG-induced PKCβ2 phosphorylation. Inhibition of PKCβ2 activation by compound CGP53353 or knockdown of PKCβ2 expression via siRNA attenuated the reductions of Cav-3 expression and Akt/endothelial nitric oxide synthase (eNOS) phosphorylation in cardiomyocytes exposed to HG. LY333531 treatment (for a duration of 4 weeks) prevented excessive PKCβ2 activation and attenuated cardiac diastolic dysfunction in rats with streptozotocin-induced diabetes. LY333531 suppressed the decreased expression of myocardial NO, Cav-3, phosphorylated (p)-Akt, and p-eNOS and also mitigated the augmentation of O2−, nitrotyrosine, Cav-1, and iNOS expression. In conclusion, hyperglycemia-induced PKCβ2 activation requires caveolae and is associated with reduced Cav-3 expression in the diabetic heart. Prevention of excessive PKCβ2 activation attenuated cardiac diastolic dysfunction by restoring Cav-3 expression and subsequently rescuing Akt/eNOS/NO signaling.

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Section: Resultsmentioning

confidence: 99%

Hyperglycemia-Induced Protein Kinase C β2 Activation Induces Diastolic Cardiac Dysfunction in Diabetic Rats by Impairing Caveolin-3 Expression and Akt/eNOS Signaling

et al. 2013

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“…In another study, it was shown that high glucose can lead to PKC β 1-mediated ROS generation through NADPH oxidase with subsequent RhoA activation in mesangial cells. This RhoA in turn activates downstream AP-1 through Rho kinase leading to activation of TGF- β 1 [195]. In consistency with these observations, Weigert et al [196] demonstrated that AP-1 activation is responsible for increased TGF- β 1 expression through PKC- and p38-MAPK-dependent pathways.…”

Section: Progression Of Renal Injury Through Diverse Signaling Patmentioning

confidence: 85%

Diabetes-Induced Reactive Oxygen Species: Mechanism of Their Generation and Role in Renal Injury

Fakhruddin

Alanazi

Jackson

2017

Journal of Diabetes Research

235

177

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Diabetes induces the onset and progression of renal injury through causing hemodynamic dysregulation along with abnormal morphological and functional nephron changes. The most important event that precedes renal injury is an increase in permeability of plasma proteins such as albumin through a damaged glomerular filtration barrier resulting in excessive urinary albumin excretion (UAE). Moreover, once enhanced UAE begins, it may advance renal injury from progression of abnormal renal hemodynamics, increased glomerular basement membrane (GBM) thickness, mesangial expansion, extracellular matrix accumulation, and glomerulosclerosis to eventual end-stage renal damage. Interestingly, all these pathological changes are predominantly driven by diabetes-induced reactive oxygen species (ROS) and abnormal downstream signaling molecules. In diabetic kidney, NADPH oxidase (enzymatic) and mitochondrial electron transport chain (nonenzymatic) are the prominent sources of ROS, which are believed to cause the onset of albuminuria followed by progression to renal damage through podocyte depletion. Chronic hyperglycemia and consequent ROS production can trigger abnormal signaling pathways involving diverse signaling mediators such as transcription factors, inflammatory cytokines, chemokines, and vasoactive substances. Persistently, increased expression and activation of these signaling molecules contribute to the irreversible functional and structural changes in the kidney resulting in critically decreased glomerular filtration rate leading to eventual renal failure.

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“…Cav-1 is a major multifunctional scaf- folding protein of caveolae that serves as a negative or positive modulator of cell signaling pathways by directly interacting with signaling molecules [28,29] . Cav-1 is an important regulatory molecule in the kidneys that is primarily expressed in mesangial cells [17,[30][31][32] , renal proximal tubule cells [33,34] and podocytes [35] . Recently, many studies have demonstrated that the functional connections between cav-1 and ROS play a key role in many diseases.…”

Section: Discussionmentioning

confidence: 99%

“…Martinez-Outschoorn et al demonstrated that a loss of stromal cav-1 in fibroblasts was sufficient to induce ROS production and oxidative stress, indicating that a loss of cav-1 provided a feed-forward mechanism for promoting oxidative stress and the autophagic program [37][38][39] . Zhang et al showed that glucose-induced ROS generation was significantly attenuated by the chemical disruption of caveolae in knockout mesangial cells [30] . Shiroto et al showed that mitochondrial ROS production was increased in endothelial cells after cav-1 knockdown, and their results established that cav-1 plays a key role in regulating oxidative stress in the endothelium and may represent a critical target in cardiovascular diseases [40] .…”

Section: Discussionmentioning

confidence: 99%

Curcumin attenuates high glucose-induced podocyte apoptosis by regulating functional connections between caveolin-1 phosphorylation and ROS

et al. 2016

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Aim: Caveolin-1 (cav-1) is a major multifunctional scaffolding protein of caveolae. Cav-1 is primarily expressed in mesangial cells, renal proximal tubule cells and podocytes in kidneys. Recent evidence shows that the functional connections between cav-1 and ROS play a key role in many diseases. In this study we investigated whether regulating the functional connections between cav-1 and ROS in kidneys contributed to the beneficial effects of curcumin in treating diabetic nephropathy in vitro and in vivo. Methods: Cultured mouse podocytes (mpc5) were incubated in a high glucose (HG, 30 mmol/L) medium for 24, 48 or 72 h. Male rats were injected with STZ (60 mg/kg, ip) to induce diabetes. ROS generation, SOD activity, MDA content and caspase-3 activity in the cultured cells and kidney cortex homogenate were determined. Apoptotic proteins and cav-1 phosphorylation were analyzed using Western blot analyses. Results: Incubation in HG-containing medium time-dependently increased ROS production, oxidative stress, apoptosis, and cav-1 phosphorylation in podocytes. Pretreatment with curcumin (1, 5, and 10 μmol/L) dose-dependently attenuated these abnormalities in HG-treated podocytes. Furthermore, in HG-containing medium, the podocytes transfected with a recombinant plasmid GFP-cav-1 Y14F (mutation at a cav-1 phosphorylation site) exhibited significantly decreased ROS production and apoptosis compared with the cells transfected with empty vector. In diabetic rats, administration of curcumin (100 or 200 mg/kg body weight per day, ig, for 8 weeks) not only significantly improved the renal function, but also suppressed ROS levels, oxidative stress, apoptosis and cav-1 phosphorylation in the kidneys. Conclusion: Curcumin attenuates high glucose-induced podocyte apoptosis in vitro and diabetic nephropathy in vivo partly through regulating the functional connections between cav-1 phosphorylation and ROS.

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High glucose-induced RhoA activation requires caveolae and PKCβ1-mediated ROS generation

Abstract: Ingram AJ, Krepinsky JC. High glucose-induced RhoA activation requires caveolae and PKC␤1-mediated ROS generation.

Cited by 30 publications

References 62 publications

Hyperglycemia-Induced Protein Kinase C β2 Activation Induces Diastolic Cardiac Dysfunction in Diabetic Rats by Impairing Caveolin-3 Expression and Akt/eNOS Signaling

Hyperglycemia-Induced Protein Kinase C β2 Activation Induces Diastolic Cardiac Dysfunction in Diabetic Rats by Impairing Caveolin-3 Expression and Akt/eNOS Signaling

Diabetes-Induced Reactive Oxygen Species: Mechanism of Their Generation and Role in Renal Injury

Curcumin attenuates high glucose-induced podocyte apoptosis by regulating functional connections between caveolin-1 phosphorylation and ROS

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