Histone H3 serine 10 phosphorylation facilitates endothelial activation in diabetic kidney disease

Tamadher A. Alghamdi; Sri N. Batchu; Mitchell J. Hadden; Veera Ganesh Yerra; Youan Liu; Bridgit B. Bowskill; Suzanne L. Advani; Laurette Geldenhuys; Ferhan S. Siddiqi; Syamantak Majumder; Andrew Advani

doi:10.2337/db18-0124

Histone H3 serine 10 phosphorylation facilitates endothelial activation in diabetic kidney disease

Tamadher A. Alghamdi, Sri N. Batchu, Mitchell J. Hadden, Veera Ganesh Yerra, Youan Liu, Bridgit B. Bowskill, Suzanne L. Advani, Laurette Geldenhuys, Ferhan S. Siddiqi, Syamantak Majumder, Andrew Advani

Medicine

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35 Citas (Scopus)

Resumen

The posttranslational histone modifications that epige-netically affect gene transcription extend beyond conventionally studied methylation and acetylation patterns. By examining the means by which podocytes influence the glomerular endothelial phenotype, we identified a role for phosphorylation of histone H3 on serine residue 10 (phospho-histone H3Ser10) in mediating endothelial activation in diabetes. Culture media conditioned by podocytes exposed to high glucose caused glomerular endothelial vascular cell adhesion protein 1 (VCAM-1) upregulation and was enriched for the chemokine CCL2. A neutralizing anti-CCL2 antibody prevented VCAM-1 upregulation in cultured glomerular endothelial cells, and knockout of the CCL2 receptor CCR2 diminished glomerular VCAM-1 upregulation in diabetic mice. CCL2/CCR2 signaling induced glomerular endothelial VCAM-1 upregulation through a pathway regulated by p38 mitogen-activated protein kinase, mitogen- and stress-activated protein kinases 1/2 (MSK1/2), and phosphorylation of H3Ser10, whereas MSK1/2 inhibition decreased H3Ser10 phosphorylation at the VCAM1 promoter. Finally, increased phospho-histone H3Ser10 levels were observed in the kidneys of diabetic endothelial nitric oxide synthase knockout mice and in the glomeruli of humans with diabetic kidney disease. These findings demonstrate the influence that histone protein phosphorylation may have on gene activation in diabetic kidney disease. Histone protein phosphorylation should be borne in mind when considering epigenetic targets amenable to therapeutic manipulation in diabetes.

Idioma original	English
Páginas (desde-hasta)	2668-2681
Número de páginas	14
Publicación	Diabetes
Volumen	67
N.º	12
DOI	https://doi.org/10.2337/db18-0124
Estado	Published - dic. 1 2018

Nota bibliográfica

Funding Information:
Acknowledgments. The authors thank Dr. Hana Klassen Vakili (currently affiliated with the Department of Pathology, University of Texas Southwestern Medical Center, TX) for technical assistance. Funding. T.A.A. is supported by a King Abdullah Foreign Scholarship. S.N.B. was supported by the Kidney Foundation of Canada through a Keenan Family Foundation Kidney Research Scientist Core Education and National Training Program Post-Doctoral fellowship, a Heart and Stroke/Richard Lewar Center of Excellence fellowship, and a Banting & Best Diabetes Centre, University of Toronto, postdoctoral fellowship. M.J.H. is a recipient of a St. Michael’s Hospital scholarship from the Research Training Centre and a Banting & Best Diabetes Centre-Novo Nordisk studentship. S.M. and A.A. were supported by a Diabetes Canada postdoctoral fellowship and diabetes investigator award, respectively. These studies were supported by a Canadian Institutes of Health Research operating grant (MOP-133631) and in part by a Heart and Stoke Foundation of Canada grant-in-aid (G-17-0018231) to A.A. Duality of Interest. A.A. has received research support through his institution from AstraZeneca and Boehringer Ingelheim and is listed as an inventor on an unrelated patent application by Boehringer Ingelheim. No other potential conflicts of interest relevant to this article were reported. Author Contributions. T.A.A. designed and performed the experiments, analyzed the data, and wrote the manuscript. S.N.B. and S.M. designed and performed the experiments and analyzed the data. M.J.H., V.G.Y., Y.L., B.B.B., and S.L.A. performed the experiments. L.G. and F.S.S. contributed to the human data. A.A. designed the experiments, supervised the study, and wrote the manuscript. A.A. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Prior Presentation. Parts of this work were presented at the World Diabetes Congress, Vancouver, British Columbia, Canada, 30 November–4 December 2015, and the 78th Scientific Sessions of the American Diabetes Association, Orlando, FL, 7–11 June 2018.

Publisher Copyright:
© 2018 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license..

ASJC Scopus Subject Areas

Internal Medicine
Endocrinology, Diabetes and Metabolism

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title = "Histone H3 serine 10 phosphorylation facilitates endothelial activation in diabetic kidney disease",

abstract = "The posttranslational histone modifications that epige-netically affect gene transcription extend beyond conventionally studied methylation and acetylation patterns. By examining the means by which podocytes influence the glomerular endothelial phenotype, we identified a role for phosphorylation of histone H3 on serine residue 10 (phospho-histone H3Ser10) in mediating endothelial activation in diabetes. Culture media conditioned by podocytes exposed to high glucose caused glomerular endothelial vascular cell adhesion protein 1 (VCAM-1) upregulation and was enriched for the chemokine CCL2. A neutralizing anti-CCL2 antibody prevented VCAM-1 upregulation in cultured glomerular endothelial cells, and knockout of the CCL2 receptor CCR2 diminished glomerular VCAM-1 upregulation in diabetic mice. CCL2/CCR2 signaling induced glomerular endothelial VCAM-1 upregulation through a pathway regulated by p38 mitogen-activated protein kinase, mitogen- and stress-activated protein kinases 1/2 (MSK1/2), and phosphorylation of H3Ser10, whereas MSK1/2 inhibition decreased H3Ser10 phosphorylation at the VCAM1 promoter. Finally, increased phospho-histone H3Ser10 levels were observed in the kidneys of diabetic endothelial nitric oxide synthase knockout mice and in the glomeruli of humans with diabetic kidney disease. These findings demonstrate the influence that histone protein phosphorylation may have on gene activation in diabetic kidney disease. Histone protein phosphorylation should be borne in mind when considering epigenetic targets amenable to therapeutic manipulation in diabetes.",

author = "Alghamdi, {Tamadher A.} and Batchu, {Sri N.} and Hadden, {Mitchell J.} and Yerra, {Veera Ganesh} and Youan Liu and Bowskill, {Bridgit B.} and Advani, {Suzanne L.} and Laurette Geldenhuys and Siddiqi, {Ferhan S.} and Syamantak Majumder and Andrew Advani",

note = "Funding Information: Acknowledgments. The authors thank Dr. Hana Klassen Vakili (currently affiliated with the Department of Pathology, University of Texas Southwestern Medical Center, TX) for technical assistance. Funding. T.A.A. is supported by a King Abdullah Foreign Scholarship. S.N.B. was supported by the Kidney Foundation of Canada through a Keenan Family Foundation Kidney Research Scientist Core Education and National Training Program Post-Doctoral fellowship, a Heart and Stroke/Richard Lewar Center of Excellence fellowship, and a Banting & Best Diabetes Centre, University of Toronto, postdoctoral fellowship. M.J.H. is a recipient of a St. Michael{\textquoteright}s Hospital scholarship from the Research Training Centre and a Banting & Best Diabetes Centre-Novo Nordisk studentship. S.M. and A.A. were supported by a Diabetes Canada postdoctoral fellowship and diabetes investigator award, respectively. These studies were supported by a Canadian Institutes of Health Research operating grant (MOP-133631) and in part by a Heart and Stoke Foundation of Canada grant-in-aid (G-17-0018231) to A.A. Duality of Interest. A.A. has received research support through his institution from AstraZeneca and Boehringer Ingelheim and is listed as an inventor on an unrelated patent application by Boehringer Ingelheim. No other potential conflicts of interest relevant to this article were reported. Author Contributions. T.A.A. designed and performed the experiments, analyzed the data, and wrote the manuscript. S.N.B. and S.M. designed and performed the experiments and analyzed the data. M.J.H., V.G.Y., Y.L., B.B.B., and S.L.A. performed the experiments. L.G. and F.S.S. contributed to the human data. A.A. designed the experiments, supervised the study, and wrote the manuscript. A.A. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Prior Presentation. Parts of this work were presented at the World Diabetes Congress, Vancouver, British Columbia, Canada, 30 November–4 December 2015, and the 78th Scientific Sessions of the American Diabetes Association, Orlando, FL, 7–11 June 2018. Publisher Copyright: {\textcopyright} 2018 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license..",

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AU - Batchu, Sri N.

AU - Hadden, Mitchell J.

AU - Yerra, Veera Ganesh

AU - Liu, Youan

AU - Bowskill, Bridgit B.

AU - Advani, Suzanne L.

AU - Geldenhuys, Laurette

AU - Siddiqi, Ferhan S.

AU - Majumder, Syamantak

AU - Advani, Andrew

N1 - Funding Information: Acknowledgments. The authors thank Dr. Hana Klassen Vakili (currently affiliated with the Department of Pathology, University of Texas Southwestern Medical Center, TX) for technical assistance. Funding. T.A.A. is supported by a King Abdullah Foreign Scholarship. S.N.B. was supported by the Kidney Foundation of Canada through a Keenan Family Foundation Kidney Research Scientist Core Education and National Training Program Post-Doctoral fellowship, a Heart and Stroke/Richard Lewar Center of Excellence fellowship, and a Banting & Best Diabetes Centre, University of Toronto, postdoctoral fellowship. M.J.H. is a recipient of a St. Michael’s Hospital scholarship from the Research Training Centre and a Banting & Best Diabetes Centre-Novo Nordisk studentship. S.M. and A.A. were supported by a Diabetes Canada postdoctoral fellowship and diabetes investigator award, respectively. These studies were supported by a Canadian Institutes of Health Research operating grant (MOP-133631) and in part by a Heart and Stoke Foundation of Canada grant-in-aid (G-17-0018231) to A.A. Duality of Interest. A.A. has received research support through his institution from AstraZeneca and Boehringer Ingelheim and is listed as an inventor on an unrelated patent application by Boehringer Ingelheim. No other potential conflicts of interest relevant to this article were reported. Author Contributions. T.A.A. designed and performed the experiments, analyzed the data, and wrote the manuscript. S.N.B. and S.M. designed and performed the experiments and analyzed the data. M.J.H., V.G.Y., Y.L., B.B.B., and S.L.A. performed the experiments. L.G. and F.S.S. contributed to the human data. A.A. designed the experiments, supervised the study, and wrote the manuscript. A.A. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Prior Presentation. Parts of this work were presented at the World Diabetes Congress, Vancouver, British Columbia, Canada, 30 November–4 December 2015, and the 78th Scientific Sessions of the American Diabetes Association, Orlando, FL, 7–11 June 2018. Publisher Copyright: © 2018 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license..

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AB - The posttranslational histone modifications that epige-netically affect gene transcription extend beyond conventionally studied methylation and acetylation patterns. By examining the means by which podocytes influence the glomerular endothelial phenotype, we identified a role for phosphorylation of histone H3 on serine residue 10 (phospho-histone H3Ser10) in mediating endothelial activation in diabetes. Culture media conditioned by podocytes exposed to high glucose caused glomerular endothelial vascular cell adhesion protein 1 (VCAM-1) upregulation and was enriched for the chemokine CCL2. A neutralizing anti-CCL2 antibody prevented VCAM-1 upregulation in cultured glomerular endothelial cells, and knockout of the CCL2 receptor CCR2 diminished glomerular VCAM-1 upregulation in diabetic mice. CCL2/CCR2 signaling induced glomerular endothelial VCAM-1 upregulation through a pathway regulated by p38 mitogen-activated protein kinase, mitogen- and stress-activated protein kinases 1/2 (MSK1/2), and phosphorylation of H3Ser10, whereas MSK1/2 inhibition decreased H3Ser10 phosphorylation at the VCAM1 promoter. Finally, increased phospho-histone H3Ser10 levels were observed in the kidneys of diabetic endothelial nitric oxide synthase knockout mice and in the glomeruli of humans with diabetic kidney disease. These findings demonstrate the influence that histone protein phosphorylation may have on gene activation in diabetic kidney disease. Histone protein phosphorylation should be borne in mind when considering epigenetic targets amenable to therapeutic manipulation in diabetes.

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Histone H3 serine 10 phosphorylation facilitates endothelial activation in diabetic kidney disease

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