NADPH Oxidase 4 Induces Cardiac Fibrosis and Hypertrophy Through Activating Akt/mTOR and NFκB Signaling Pathways

Zhao, Qiu; Viswanadhapalli, Suryavathi; Williams, Paul J.; Shi, Qian; Tan, Chunyan; Yi, Xiaolan; Bhandari, Basant; Abboud, Hanna E.

doi:10.1161/circulationaha.114.011079

Cited by 212 publications

(158 citation statements)

References 56 publications

Supporting

Mentioning

148

Contrasting

Order By: Relevance

“…A recent study, albeit in the heart, supports our findings that NOX4 plays a role in fibrosis and hypertrophy [34]. In that study, NOX4 was shown to induce cardiac fibrosis and hypertrophy via activation of the Akt/mTOR and nuclear factor-κB signalling pathways [34].…”

Section: Discussionsupporting

confidence: 79%

Podocyte-specific Nox4 deletion affords renoprotection in a mouse model of diabetic nephropathy

et al. 2015

View full text Add to dashboard Cite

Aims/hypothesis Changes in podocyte morphology and function are associated with albuminuria and progression of diabetic nephropathy. NADPH oxidase 4 (NOX4) is the main source of reactive oxygen species (ROS) in the kidney and Nox4 is upregulated in podocytes in response to high glucose. We assessed the role of NOX4-derived ROS in podocytes in vivo in a model of diabetic nephropathy using a podocyte-specific NOX4-deficient mouse, with a major focus on the development of albuminuria and ultra-glomerular structural damage. Methods Streptozotocin-induced diabetes-associated changes in renal structure and function were studied in male floxedNox4 and podocyte-specific, NOX4 knockout (podNox4KO) mice. We assessed albuminuria, glomerular extracellular matrix accumulation and glomerulosclerosis, and markers of ROS and inflammation, as well as glomerular basement membrane thickness, effacement of podocytes and expression of the podocyte-specific protein nephrin. Results Podocyte-specific Nox4 deletion in streptozotocininduced diabetic mice attenuated albuminuria in association with reduced vascular endothelial growth factor (VEGF) expression and prevention of the diabetes-induced reduction in nephrin expression. In addition, podocyte-specific Nox4 deletion reduced glomerular accumulation of collagen IV and fibronectin, glomerulosclerosis and mesangial expansion, as well as glomerular basement membrane thickness. Furthermore, diabetes-induced increases in renal ROS, glomerular monocyte chemoattractant protein-1 (MCP-1) and protein kinase C alpha (PKC-α) were attenuated in podocyte-specific NOX4-deficient mice. Conclusions/interpretation Collectively, this study shows the deleterious effect of Nox4 expression in podocytes by promoting podocytopathy in association with albuminuria and extracellular matrix accumulation in experimental diabetes, emphasising the role of NOX4 as a target for new renoprotective agents. Electronic supplementary material The online version of this article (doi:10.1007/s00125-015-3796-0) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

show abstract

Section: Discussionsupporting

confidence: 79%

Podocyte-specific Nox4 deletion affords renoprotection in a mouse model of diabetic nephropathy

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Our current study cannot exclude the possibility that plumbagin attenuates IL-1β secretion partly by inhibiting NF-κB activation, which is required for increased PKM2 expression in epidermal growth factor-induced glycolysis in cancer cells (44). Furthermore, NOX4 is required for activation of NF-κB in response to hypoxia and LPS (45,46). It is possible that the NOX4-mediated PKM2 expression may depend on the activation of NF-κB in LPS-induced macrophages.…”

Section: Discussionmentioning

confidence: 73%

Plumbagin Protects Mice from Lethal Sepsis by Modulating Immunometabolism Upstream of PKM2

Zhang

Deng

Kang

et al. 2016

Mol Med

View full text Add to dashboard Cite

Sepsis is characterized by dysregulated systemic inflammation with release of early (for example, interleukin (IL)-1β) and late (for example, HMGB1) proinflammatory mediators from macrophages. Plumbagin, a medicinal plant-derived naphthoquinone, has been reported to exhibit antiinflammatory activity, but the underling mechanisms remain unclear. Here, we have demonstrated that plumbagin inhibits the inflammatory response through interfering with the immunometabolism pathway in activated macrophages. Remarkably, plumbagin inhibited lipopolysaccharide (LPS)-induced aerobic glycolysis by downregulating the expression of pyruvate kinase M2 (PKM2), a protein kinase responsible for the final and rate-limiting reaction step of the glycolytic pathway. Moreover, the NADPH oxidase 4 (NOX4)-mediated oxidative stress was required for LPS-induced PKM2 expression, because pharmacologic or genetic inhibition of NOX4 by plumbagin or RNA interference limited LPS-induced PKM2 expression, lactate production and subsequent proinflammatory cytokine (IL-1β and HMGB1) release in macrophages. Finally, plumbagin protected mice from lethal endotoxemia and polymicrobial sepsis induced by cecal ligation and puncture. These findings identify a new approach for inhibiting the NOX4/PKM2-dependent immunometabolism pathway in the treatment of sepsis and inflammatory diseases.

show abstract

“…Previous studies demonstrated that the phosphatidyl inositol 3‐kinase–Akt signaling pathway protects the heart against injuries and is therefore called a survival factor for cardiomyocytes; however, this pathway also induces cardiac hypertrophy (Fujio et al ., 2000; Condorelli et al ., 2002; Zhao et al ., 2015). Our previous study demonstrated that EETs and CYP epoxygenases markedly activate Akt and inhibit cardiac hypertrophy (Xiao et al ., 2010).…”

Section: Resultsmentioning

confidence: 99%

CYP 2J2 and its metabolites (epoxyeicosatrienoic acids) attenuate cardiac hypertrophy by activating AMPK α2 and enhancing nuclear translocation of Akt1

et al. 2016

View full text Add to dashboard Cite

SummaryCytochrome P450 epoyxgenase 2J2 and epoxyeicosatrienoic acids (EETs) are known to protect against cardiac hypertrophy and heart failure, which involve the activation of 5′‐AMP‐activated protein kinase (AMPK) and Akt. Although the functional roles of AMPK and Akt are well established, the significance of cross talk between them in the development of cardiac hypertrophy and antihypertrophy of CYP2J2 and EETs remains unclear. We investigated whether CYP2J2 and its metabolites EETs protected against cardiac hypertrophy by activating AMPKα2 and Akt1. Moreover, we tested whether EETs enhanced cross talk between AMPKα2 and phosphorylated Akt1 (p‐Akt1), and stimulated nuclear translocation of p‐Akt1, to exert their antihypertrophic effects. AMPKα2−/− mice that overexpressed CYP2J2 in heart were treated with Ang II for 2 weeks. Interestingly, overexpression of CYP2J2 suppressed cardiac hypertrophy and increased levels of atrial natriuretic peptide (ANP) in the heart tissue and plasma of wild‐type mice but not AMPKα2−/− mice. The CYP2J2 metabolites, 11,12‐EET, activated AMPKα2 to induce nuclear translocation of p‐Akt1 selectively, which increased the production of ANP and therefore inhibited the development of cardiac hypertrophy. Furthermore, by co‐immunoprecipitation analysis, we found that AMPKα2β2γ1 and p‐Akt1 interact through the direct binding of the AMPKγ1 subunit to the Akt1 protein kinase domain. This interaction was enhanced by 11,12‐EET. Our studies reveal a novel mechanism in which CYP2J2 and EETs enhanced Akt1 nuclear translocation through interaction with AMPKα2β2γ1 and protect against cardiac hypertrophy and suggest that overexpression of CYP2J2 might have clinical potential to suppress cardiac hypertrophy and heart failure.

show abstract

NADPH Oxidase 4 Induces Cardiac Fibrosis and Hypertrophy Through Activating Akt/mTOR and NFκB Signaling Pathways

Cited by 212 publications

References 56 publications

Podocyte-specific Nox4 deletion affords renoprotection in a mouse model of diabetic nephropathy

Podocyte-specific Nox4 deletion affords renoprotection in a mouse model of diabetic nephropathy

Plumbagin Protects Mice from Lethal Sepsis by Modulating Immunometabolism Upstream of PKM2

CYP 2J2 and its metabolites (epoxyeicosatrienoic acids) attenuate cardiac hypertrophy by activating AMPK α2 and enhancing nuclear translocation of Akt1

Contact Info

Product

Resources

About