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105. Targeted deletion of nicotinamide adenine dinucleotide phosphate oxidase 4 from proximal tubules is dispensable for diabetic kidney disease development.

Author

Thallas-Bonke, Vicki, Tan, Sih Min, Lindblom, Runa S, Snelson, Matthew, Granata, Cesare, Jha, Jay Chandra, Sourris, Karly C, Laskowski, Adrienne, Watson, Anna, Tauc, Michel, Rubera, Isabelle, Zheng, Guoping, Shah, Ajay M, Harris, David C H, Elbatreek, Mahmoud H, Kantharidis, Phillip, Cooper, Mark E, Jandeleit-Dahm, Karin, and Coughlan, Melinda T

Subjects
DIABETIC nephropathies, NICOTINAMIDE adenine dinucleotide phosphate, KIDNEY development, RENAL fibrosis, LABORATORY mice
Abstract

Background The nicotinamide adenine dinucleotide phosphate oxidase isoform 4 (Nox4) mediates reactive oxygen species (ROS) production and renal fibrosis in diabetic kidney disease (DKD) at the level of the podocyte. However, the mitochondrial localization of Nox4 and its role as a mitochondrial bioenergetic sensor has recently been reported. Whether Nox4 drives pathology in DKD within the proximal tubular compartment, which is densely packed with mitochondria, is not yet known. Methods We generated a proximal tubular–specific Nox4 knockout mouse model by breeding Nox4flox/flox mice with mice expressing Cre recombinase under the control of the sodium–glucose cotransporter-2 promoter. Subsets of Nox4ptKO mice and their Nox4flox/flox littermates were injected with streptozotocin (STZ) to induce diabetes. Mice were followed for 20 weeks and renal injury was assessed. Results Genetic ablation of proximal tubular Nox4 (Nox4ptKO) resulted in no change in renal function and histology. Nox4ptKO mice and Nox4flox/flox littermates injected with STZ exhibited the hallmarks of DKD, including hyperfiltration, albuminuria, renal fibrosis and glomerulosclerosis. Surprisingly, diabetes-induced renal injury was not improved in Nox4ptKO STZ mice compared with Nox4flox/flox STZ mice. Although diabetes conferred ROS overproduction and increased the mitochondrial oxygen consumption rate, proximal tubular deletion of Nox4 did not normalize oxidative stress or mitochondrial bioenergetics. Conclusions Taken together, these results demonstrate that genetic deletion of Nox4 from the proximal tubules does not influence DKD development, indicating that Nox4 localization within this highly energetic compartment is dispensable for chronic kidney disease pathogenesis in the setting of diabetes. [ABSTRACT FROM AUTHOR]

Published
2021
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111. Transactivation of RAGE mediates angiotensin-induced inflammation and atherogenesis

Author

Pickering, Raelene J., primary, Tikellis, Christos, additional, Rosado, Carlos J., additional, Tsorotes, Despina, additional, Dimitropoulos, Alexandra, additional, Smith, Monique, additional, Huet, Olivier, additional, Seeber, Ruth M., additional, Abhayawardana, Rekhati, additional, Johnstone, Elizabeth K.M., additional, Golledge, Jonathan, additional, Wang, Yutang, additional, Jandeleit-Dahm, Karin A., additional, Cooper, Mark E., additional, Pfleger, Kevin D.G., additional, and Thomas, Merlin C., additional

Published
2018
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112. Endothelium-restricted endothelin-1 overexpression in type 1 diabetes worsens atherosclerosis and immune cell infiltration via NOX1.

Author

Ouerd, Sofiane, Idris-Khodja, Noureddine, Trindade, Michelle, Ferreira, Nathanne S, Berillo, Olga, Coelho, Suellen C, Neves, Mario F, Jandeleit-Dahm, Karin A, Paradis, Pierre, and Schiffrin, Ernesto L

Subjects
TYPE 1 diabetes, ATHEROSCLEROSIS, DIABETIC angiopathies, PREPROENDOTHELIN, THORACIC aorta, SINUS of valsalva
Abstract

Aims NADPH oxidase (NOX) 1 but not NOX4-dependent oxidative stress plays a role in diabetic vascular disease, including atherosclerosis. Endothelin (ET)-1 has been implicated in diabetes-induced vascular complications. We showed that crossing mice overexpressing human ET-1 selectively in endothelium (eET-1) with apolipoprotein E knockout (Apoe−/−) mice enhanced high-fat diet-induced atherosclerosis in part by increasing oxidative stress. We tested the hypothesis that ET-1 overexpression in the endothelium would worsen atherosclerosis in type 1 diabetes through a mechanism involving NOX1 but not NOX4. Methods and results Six-week-old male Apoe−/ − and eET-1/ Apoe−/ − mice with or without Nox1 (Nox1−/y) or Nox4 knockout (Nox4−/ − ) were injected intraperitoneally with either vehicle or streptozotocin (55 mg/kg/day) for 5 days to induce type 1 diabetes and were studied 14 weeks later. ET-1 overexpression increased 2.5-fold and five-fold the atherosclerotic lesion area in the aortic sinus and arch of diabetic Apoe−/ − mice, respectively. Deletion of Nox1 reduced aortic arch plaque size by 60%; in contrast, Nox4 knockout increased lesion size by 1.5-fold. ET-1 overexpression decreased aortic sinus and arch plaque alpha smooth muscle cell content by ∼35% and ∼50%, respectively, which was blunted by Nox1 but not Nox4 knockout. Reactive oxygen species production was increased two-fold in aortic arch perivascular fat of diabetic eET-1/ Apoe−/ − and eET-1/ Apoe−/− / Nox4−/− mice but not eET-1/ Apoe−/− / Nox1y/− mice. ET-1 overexpression enhanced monocyte/macrophage and CD3+ T-cell infiltration ∼2.7-fold in the aortic arch perivascular fat of diabetic Apoe−/ − mice. Both Nox1 and Nox4 knockout blunted CD3+ T-cell infiltration whereas only Nox1 knockout prevented the monocyte/macrophage infiltration in diabetic eET-1/ Apoe−/ − mice. Conclusion Endothelium ET-1 overexpression enhances the progression of atherosclerosis in type 1 diabetes, perivascular oxidative stress, and inflammation through NOX1. [ABSTRACT FROM AUTHOR]

Published
2021
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113. Specific NLRP3 Inhibition Protects Against Diabetes-Associated Atherosclerosis.

Author

Sharma, Arpeeta, Choi, Judy S.Y., Stefanovic, Nada, Al-Sharea, Annas, Simpson, Daniel S., Mukhamedova, Nigora, Jandeleit-Dahm, Karin, Murphy, Andrew J., Sviridov, Dmitri, Vince, James E., Ritchie, Rebecca H., and de Haan, Judy B.

Subjects
NLRP3 protein, MUSCLE cells, ATHEROSCLEROSIS, SMOOTH muscle, VASCULAR diseases, CYTOKINES
Abstract

Low-grade persistent inflammation is a feature of diabetes-driven vascular complications, in particular activation of the Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome to trigger the maturation and release of the inflammatory cytokine interleukin-1β (IL-1β). We investigated whether inhibiting the NLRP3 inflammasome, through the use of the specific small-molecule NLRP3 inhibitor MCC950, could reduce inflammation, improve vascular function, and protect against diabetes-associated atherosclerosis in the streptozotocin-induced diabetic apolipoprotein E-knockout mouse. Diabetes led to an approximately fourfold increase in atherosclerotic lesions throughout the aorta, which were significantly attenuated with MCC950 (P < 0.001). This reduction in lesions was associated with decreased monocyte-macrophage content, reduced necrotic core, attenuated inflammatory gene expression (IL-1β, tumor necrosis factor-α, intracellular adhesion molecule 1, and MCP-1; P < 0.05), and reduced oxidative stress, while maintaining fibrous cap thickness. Additionally, vascular function was improved in diabetic vessels of mice treated with MCC950 (P < 0.05). In a range of cell lines (murine bone marrow-derived macrophages, human monocytic THP-1 cells, phorbol 12-myristate 13-acetate-differentiated human macrophages, and aortic smooth muscle cells from humans with diabetes), MCC950 significantly reduced IL-1β and/or caspase-1 secretion and attenuated leukocyte-smooth muscle cell interactions under high glucose or lipopolysaccharide conditions. In summary, MCC950 reduces plaque development, promotes plaque stability, and improves vascular function, suggesting that targeting NLRP3-mediated inflammation is a novel therapeutic strategy to improve diabetes-associated vascular disease. [ABSTRACT FROM AUTHOR]

Published
2021
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114. Lipoxins regulate the early growth response-1 network and reverse diabetic Kidney disease

Author

Brennan, Eoin P., Mohan, Muthukumar, McClelland, Aaron, Tikellis, Christos, Ziemann, Mark, Kaspi, Antony, Gray, Stephen P., Pickering, Raelene, Tan, Sih Min, Ali-Shah, Syed Tasadaque, Guiry, Patrick J., El-Osta, Assam, Jandeleit-Dahm, Karin, Cooper, Mark E., Godson, Catherine, Kantharidis, Phillip, Brennan, Eoin P., Mohan, Muthukumar, McClelland, Aaron, Tikellis, Christos, Ziemann, Mark, Kaspi, Antony, Gray, Stephen P., Pickering, Raelene, Tan, Sih Min, Ali-Shah, Syed Tasadaque, Guiry, Patrick J., El-Osta, Assam, Jandeleit-Dahm, Karin, Cooper, Mark E., Godson, Catherine, and Kantharidis, Phillip

Published
2018

116. A novel synthetic small molecule DMFO targets Nrf2 in modulating proinflammatory/antioxidant mediators to ameliorate inflammation

Author

Mathew, Geetha, primary, Sharma, Arpeeta, additional, Pickering, Raelene J., additional, Rosado, Carlos J., additional, Lemarie, Jeremie, additional, Mudgal, Jayesh, additional, Thambi, Magith, additional, Sebastian, Sarine, additional, Jandeleit-Dahm, Karin A., additional, de Haan, Judy B., additional, and Unnikrishnan, Mazhuvancherry K., additional

Published
2018
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118. Lipoxins Protect Against Inflammation in Diabetes-Associated Atherosclerosis

Author

Brennan, Eoin P., primary, Mohan, Muthukumar, additional, McClelland, Aaron, additional, de Gaetano, Monica, additional, Tikellis, Christos, additional, Marai, Mariam, additional, Crean, Daniel, additional, Dai, Aozhi, additional, Beuscart, Ophelie, additional, Derouiche, Sinda, additional, Gray, Stephen P., additional, Pickering, Raelene, additional, Tan, Sih Min, additional, Godson-Treacy, Molly, additional, Sheehan, Stephen, additional, Dowdall, Joseph F., additional, Barry, Mary, additional, Belton, Orina, additional, Ali-Shah, Syed Tasadaque, additional, Guiry, Patrick J., additional, Jandeleit-Dahm, Karin, additional, Cooper, Mark E., additional, Godson, Catherine, additional, and Kantharidis, Phillip, additional

Published
2018
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122. Lipoxins Regulate the Early Growth Response–1 Network and Reverse Diabetic Kidney Disease

Author

Brennan, Eoin P., primary, Mohan, Muthukumar, additional, McClelland, Aaron, additional, Tikellis, Christos, additional, Ziemann, Mark, additional, Kaspi, Antony, additional, Gray, Stephen P., additional, Pickering, Raelene, additional, Tan, Sih Min, additional, Ali-Shah, Syed Tasadaque, additional, Guiry, Patrick J., additional, El-Osta, Assam, additional, Jandeleit-Dahm, Karin, additional, Cooper, Mark E., additional, Godson, Catherine, additional, and Kantharidis, Phillip, additional

Published
2018
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125. NADPH Oxidase Nox5 Accelerates Renal Injury in Diabetic Nephropathy

Author

Jha, Jay C., primary, Banal, Claudine, additional, Okabe, Jun, additional, Gray, Stephen P., additional, Hettige, Thushan, additional, Chow, Bryna S.M., additional, Thallas-Bonke, Vicki, additional, De Vos, Lisanne, additional, Holterman, Chet E., additional, Coughlan, Melinda T., additional, Power, David A., additional, Skene, Alison, additional, Ekinci, Elif I., additional, Cooper, Mark E., additional, Touyz, Rhian M., additional, Kennedy, Chris R., additional, and Jandeleit-Dahm, Karin, additional

Published
2017
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126. Protective Effect of let-7 miRNA Family in Regulating Inflammation in Diabetes-Associated Atherosclerosis

Author

Brennan, Eoin, primary, Wang, Bo, additional, McClelland, Aaron, additional, Mohan, Muthukumar, additional, Marai, Mariam, additional, Beuscart, Ophelie, additional, Derouiche, Sinda, additional, Gray, Stephen, additional, Pickering, Raelene, additional, Tikellis, Chris, additional, de Gaetano, Monica, additional, Barry, Mary, additional, Belton, Orina, additional, Ali-Shah, Syed Tasadaque, additional, Guiry, Patrick, additional, Jandeleit-Dahm, Karin A.M., additional, Cooper, Mark E., additional, Godson, Catherine, additional, and Kantharidis, Phillip, additional

Published
2017
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131. NOX4-derived reactive oxygen species limit fibrosis and inhibit proliferation of vascular smooth muscle cells in diabetic atherosclerosis

Author

Di Marco, Elyse, Di Marco, Elyse, Gray, Stephen P., Kennedy, Kit, Szyndralewiez, Cedric, Lyle, Alicia N., Lassegue, Bernard, Griendling, Kathy K., Cooper, Mark E., Schmidt, Harald H. H. W., Jandeleit-Dahm, Karin A. M., Di Marco, Elyse, Di Marco, Elyse, Gray, Stephen P., Kennedy, Kit, Szyndralewiez, Cedric, Lyle, Alicia N., Lassegue, Bernard, Griendling, Kathy K., Cooper, Mark E., Schmidt, Harald H. H. W., and Jandeleit-Dahm, Karin A. M.

Abstract

Smooth muscle cell (SMC) proliferation and fibrosis contribute to the development of advanced atherosclerotic lesions. Oxidative stress caused by increased production or unphysiological location of reactive oxygen species (ROS) is a known major pathomechanism. However, in atherosclerosis, in particular under hyperglycaemic/diabetic conditions, the hydrogen peroxide-producing NADPH oxidase type 4 (NOX4) is protective. Here we aim to elucidate the mechanisms underlying this paradoxical atheroprotection of vascular smooth muscle NOX4 under conditions of normo- and hyperglycaemia both in vivo and ex vivo. Following 20-weeks of streptozotocin-induced diabetes, Apoe(-/-) mice showed a reduction in SM-alpha-actin and calponin gene expression with concomitant increases in platelet-derived growth factor (PDGF), osteopontin (OPN) and the extracellular matrix (ECM) protein fibronectin when compared to non-diabetic controls. Genetic deletion of Nox4 (Nox4(-/-)Apoe(-/-)) exacerbated diabetes-induced expression of PDGF, OPN, collagen I, and proliferation marker Ki67. Aortic SMCs isolated from NOX4-deficient mice exhibited a dedifferentiated phenotype including loss of contractile gene expression, increased proliferation and ECM production as well as elevated levels of NOX1-associated ROS. Mechanistic studies revealed that elevated PDGF signalling in NOX4-deficient SMCs mediated the loss of calponin and increase in fibronectin, while the upregulation of NOX1 was associated with the increased expression of OPN and markers of proliferation. These findings demonstrate that NOX4 actively regulates SMC pathophysiological responses in diabetic Apoe(-/-) mice and in primary mouse SMCs through the activities of PDGF and NOX1.

Published
2016

132. Reactive Oxygen Species Can Provide Atheroprotection via NOX4-Dependent Inhibition of Inflammation and Vascular Remodeling

Author

Gray, Stephen P., Gray, Stephen P., Di Marco, Elyse, Kennedy, Kit, Chew, Phyllis, Okabe, Jun, El-Osta, Assam, Calkin, Anna C., Biessen, Erik A. L., Touyz, Rhian M., Cooper, Mark E., Schmidt, Harald H. H. W., Jandeleit-Dahm, Karin A. M., Gray, Stephen P., Gray, Stephen P., Di Marco, Elyse, Kennedy, Kit, Chew, Phyllis, Okabe, Jun, El-Osta, Assam, Calkin, Anna C., Biessen, Erik A. L., Touyz, Rhian M., Cooper, Mark E., Schmidt, Harald H. H. W., and Jandeleit-Dahm, Karin A. M.

Abstract

Objective Oxidative stress is considered a hallmark of atherosclerosis. In particular, the superoxide-generating type 1 NADPH oxidase (NOX1) has been shown to be induced and play a pivotal role in early phases of mouse models of atherosclerosis and in the context of diabetes mellitus. Here, we investigated the role of the most abundant type 4 isoform (NOX4) in human and mouse advanced atherosclerosis. Approach and Results Plaques of patients with cardiovascular events or established diabetes mellitus showed a surprising reduction in expression of the most abundant but hydrogen peroxide (H2O2)-generating type 4 isoform (Nox4), whereas Nox1 mRNA was elevated, when compared with respective controls. As these data suggested that NOX4-derived reactive oxygen species may convey a surprisingly protective effect during plaque progression, we examined a mouse model of accelerated and advanced diabetic atherosclerosis, the streptozotocin-treated ApoE(-/-) mouse, with (NOX4(-/-)) and without genetic deletion of Nox4. Similar to the human data, advanced versus early plaques of wild-type mice showed reduced Nox4 mRNA expression. Consistent with a rather protective role of NOX4-derived reactive oxygen species, NOX4(-/-) mice showed increased atherosclerosis when compared with wild-type mice. Deleting NOX4 was associated with reduced H2O2 forming activity and attenuation of the proinflammatory markers, monocyte chemotratic protein-1, interleukin-1, and tumor necrosis factor-, as well as vascular macrophage accumulation. Furthermore, there was a greater accumulation of fibrillar collagen fibres within the vascular wall and plaque in diabetic Nox4(-/-)ApoE(-/-) mice, indicative of plaque remodeling. These data could be replicated in human aortic endothelial cells in vitro, where Nox4 overexpression increased H2O2 and reduced the expression of pro-oxidants and profibrotic markers. Interestingly, Nox4 levels inversely correlated with Nox2 gene and protein levels. Although NOX2 is not

Published
2016

138. NOX4-derived reactive oxygen species limit fibrosis and inhibit proliferation of vascular smooth muscle cells in diabetic atherosclerosis

Author

Di Marco, Elyse, primary, Gray, Stephen P., additional, Kennedy, Kit, additional, Szyndralewiez, Cedric, additional, Lyle, Alicia N., additional, Lassègue, Bernard, additional, Griendling, Kathy K., additional, Cooper, Mark E., additional, Schmidt, Harald H.H.W., additional, and Jandeleit-Dahm, Karin A.M., additional

Published
2016
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140. Reactive Oxygen Species Can Provide Atheroprotection via NOX4-Dependent Inhibition of Inflammation and Vascular Remodeling

Author

Gray, Stephen P., primary, Di Marco, Elyse, additional, Kennedy, Kit, additional, Chew, Phyllis, additional, Okabe, Jun, additional, El-Osta, Assam, additional, Calkin, Anna C., additional, Biessen, Erik A.L., additional, Touyz, Rhian M., additional, Cooper, Mark E., additional, Schmidt, Harald H.H.W., additional, and Jandeleit-Dahm, Karin A.M., additional

Published
2016
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141. CXCR4 Antagonism attenuates the development of diabetic cardiac fibrosis

Author

Chu, Po-Yin, Walder, Ken, Horlock, Duncan, Williams, David, Nelson, Erin, Byrne, Melissa, Jandeleit-Dahm, Karin, Zimmet, Paul, Kaye, David M., Chu, Po-Yin, Walder, Ken, Horlock, Duncan, Williams, David, Nelson, Erin, Byrne, Melissa, Jandeleit-Dahm, Karin, Zimmet, Paul, and Kaye, David M.

Abstract

Heart failure (HF) is an increasingly recognized complication of diabetes. Cardiac fibrosis is an important causative mechanism of HF associated with diabetes. Recent data indicate that inflammation may be particularly important in the pathogenesis of cardiovascular fibrosis. We sought to determine the mechanism by which cardiac fibrosis develops and to specifically investigate the role of the CXCR4 axis in this process. Animals with type I diabetes (streptozotocin treated mice) or type II diabetes (Israeli Sand-rats) and controls were randomized to treatment with a CXCR4 antagonist, candesartan or vehicle control. Additional groups of mice also underwent bone marrow transplantation (GFP+ donor marrow) to investigate the potential role of bone marrow derived cell mobilization in the pathogenesis of cardiac fibrosis. Both type I and II models of diabetes were accompanied by the development of significant cardiac fibrosis. CXCR4 antagonism markedly reduced cardiac fibrosis in both models of diabetes, similar in magnitude to that seen with candesartan. In contrast to candesartan, the anti-fibrotic actions of CXCR4 antagonism occurred in a blood pressure independent manner. Whilst the induction of diabetes did not increase the overall myocardial burden of GFP+ cells, it was accompanied by an increase in GFP+ cells expressing the fibroblast marker alpha-smooth muscle actin and this was attenuated by CXCR4 antagonism. CXCR4 antagonism was also accompanied by increased levels of circulating regulatory T cells. Taken together the current data indicate that pharmacological inhibition of CXCR4 significantly reduces diabetes induced cardiac fibrosis, providing a potentially important therapeutic approach.

Published
2015

143. Correction: Diabetic kidney disease

Author

Thomas, Merlin C., primary, Brownlee, Michael, additional, Susztak, Katalin, additional, Sharma, Kumar, additional, Jandeleit-Dahm, Karin A. M., additional, Zoungas, Sophia, additional, Rossing, Peter, additional, Groop, Per-Henrik, additional, and Cooper, Mark E., additional

Published
2015
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146. Abstract 698: Increases Reticulated Platelets due to Enhanced Proliferation and Expansion of Bone Marrow Megakaryocyte Progenitors Accelerates Atherosclerosis in Diabetes

Author

Kraakman, Michael J, primary, Dragoljevic, Dragana, additional, Hanssen, Nordin M, additional, Jandeleit-Dahm, Karin, additional, Kile, Benjamin T, additional, Josefsson, Emma, additional, Febbraio, Mark A, additional, Chin-Dusting, Jaye P, additional, Cooper, Mark E, additional, Nagareddy, Prabhakara R, additional, Goldberg, Ira J, additional, and Murphy, Andrew J, additional

Published
2015
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149. HMGB1 binds to activated platelets via the receptor for advanced glycation end products and is present in platelet rich human coronary artery thrombi

Author

Bode, Michael, primary, Haenel, David, primary, Hagemeyer, Christoph E., primary, Seeba, Hannah, primary, Duerschmied, Daniel, primary, Bassler, Nicole, primary, Jandeleit-Dahm, Karin A., primary, Sweet, Matthew J., primary, Agrotis, Alex, primary, Bobik, Alex, primary, Peter, Karlheinz, primary, Ahrens, Ingo, additional, Chen, Yung-Chih, additional, and Topcic, Danijal, additional

Published
2015
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