Set7 Methyltransferase and Phenotypic Switch in Diabetic Glomerular Endothelial Cells

Scott Maxwell; Jun Okabe; Harikrishnan Kaipananickal; Hanah Rodriguez; Ishant Khurana; Keith Al-Hasani; Bryna S.M. Chow; Eleni Pitsillou; Tom C. Karagiannis; Karin Jandeleit-Dahm; Ronald C.W. Ma; Yu Huang; Juliana C.N. Chan; Mark E. Cooper; Assam El-Osta

doi:10.1681/ASN.0000000000000345

Set7 Methyltransferase and Phenotypic Switch in Diabetic Glomerular Endothelial Cells

Scott Maxwell
, Jun Okabe
, Harikrishnan Kaipananickal
, Hanah Rodriguez
, Ishant Khurana
, Keith Al-Hasani
, Bryna S.M. Chow
, Eleni Pitsillou
, Tom C. Karagiannis
, Karin Jandeleit-Dahm
, Ronald C.W. Ma
, Yu Huang
, Juliana C.N. Chan
, Mark E. Cooper
, Assam El-Osta^*

^*Corresponding author for this work

Department of Biomedical Sciences

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

17 Citations (Scopus)

68 Downloads (CityUHK Scholars)

Abstract

Background Hyperglycemia influences the development of glomerular endothelial cell damage, and nowhere is this more evident than in the progression of diabetic kidney disease (DKD). While the Set7 lysine methyltransferase is a known hyperglycemic sensor, its role in endothelial cell function in the context of DKD remains poorly understood.
Methods Single-cell transcriptomics was used to investigate Set7 regulation in a mouse model of DKD, followed by validation of findings using pharmacological and short hairpin RNA inhibition inhibition of Set7.
Results Set7 knockout (Set7KO) improved glomerular structure and albuminuria in a mouse model of diabetes. Analysis of single-cell RNA-sequencing data showed dynamic transcriptional changes in diabetic renal cells. Set7KO controls phenotype switching of glomerular endothelial cell populations by transcriptional regulation of the insulin growth factor binding protein 5 (IGFBP5). Chromatin immunoprecipitation assays confirmed that the expression of the IGFBP5 gene was associated with mono- and dimethylation of histone H3 lysine 4 (H3K4me1/2). This generalizability was investigated in human kidney and circulating hyperglycemic cells exposed to TGFβ1. We showed that the highly selective Set7 inhibitor (R)-PFI-2 hydrochloride attenuated indices associated with renal cell damage and mesenchymal transition, specifically (1) reactive oxygen species production, (2) IGFBP5 gene regulation, and (3) expression of mesenchymal markers. Furthermore, renal benefit observed in Set7KO diabetic mice closely corresponded in human glomerular endothelial cells with (R)-PFI-2 hydrochloride inhibition or Set7 short hairpin RNA silencing.
Conclusions Set7 regulates the phenotypic endothelial-mesenchymal transition switch and suggests that targeting the lysine methyltransferase could protect glomerular cell injury in DKD.
© 2024 Wolters Kluwer Health. All rights reserved.

Original language	English
Pages (from-to)	733-748
Journal	Journal of the American Society of Nephrology
Volume	35
Issue number	6
Online published	17 Apr 2024
DOIs	https://doi.org/10.1681/ASN.0000000000000345
Publication status	Published - Jun 2024

Funding

A. El-Osta: National Health and Medical Research Council (1154650, 0526681, and 2014763). National Health and Medical Research Council (1142262, 1078609, and 1027341) and National Science Foundation of China (81561128017). R.C.W. Ma: Research Grants Council Impact Fund (R4012-18). Y. Huang: RGC-Senior Research Fellow Scheme (SRFS2021-4S04).

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Research Keywords

diabetes
diabetes mellitus
diabetic kidney disease
diabetic nephropathy
endothelium
gene expression
gene transcription

Publisher's Copyright Statement

This full text is made available under CC-BY 4.0. https://creativecommons.org/licenses/by/4.0/

RGC Funding Information

RGC-funded

Access Output

10.1681/ASN.0000000000000345

229068245.pdfFinal Published version, 41.4 MBLicence: CC BY

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Maxwell, S., Okabe, J., Kaipananickal, H., Rodriguez, H., Khurana, I., Al-Hasani, K., Chow, B. S. M., Pitsillou, E., Karagiannis, T. C., Jandeleit-Dahm, K., Ma, R. C. W., Huang, Y., Chan, J. C. N., Cooper, M. E., & El-Osta, A. (2024). Set7 Methyltransferase and Phenotypic Switch in Diabetic Glomerular Endothelial Cells. Journal of the American Society of Nephrology, 35(6), 733-748. https://doi.org/10.1681/ASN.0000000000000345

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title = "Set7 Methyltransferase and Phenotypic Switch in Diabetic Glomerular Endothelial Cells",

abstract = "Background Hyperglycemia influences the development of glomerular endothelial cell damage, and nowhere is this more evident than in the progression of diabetic kidney disease (DKD). While the Set7 lysine methyltransferase is a known hyperglycemic sensor, its role in endothelial cell function in the context of DKD remains poorly understood. Methods Single-cell transcriptomics was used to investigate Set7 regulation in a mouse model of DKD, followed by validation of findings using pharmacological and short hairpin RNA inhibition inhibition of Set7. Results Set7 knockout (Set7KO) improved glomerular structure and albuminuria in a mouse model of diabetes. Analysis of single-cell RNA-sequencing data showed dynamic transcriptional changes in diabetic renal cells. Set7KO controls phenotype switching of glomerular endothelial cell populations by transcriptional regulation of the insulin growth factor binding protein 5 (IGFBP5). Chromatin immunoprecipitation assays confirmed that the expression of the IGFBP5 gene was associated with mono- and dimethylation of histone H3 lysine 4 (H3K4me1/2). This generalizability was investigated in human kidney and circulating hyperglycemic cells exposed to TGFβ1. We showed that the highly selective Set7 inhibitor (R)-PFI-2 hydrochloride attenuated indices associated with renal cell damage and mesenchymal transition, specifically (1) reactive oxygen species production, (2) IGFBP5 gene regulation, and (3) expression of mesenchymal markers. Furthermore, renal benefit observed in Set7KO diabetic mice closely corresponded in human glomerular endothelial cells with (R)-PFI-2 hydrochloride inhibition or Set7 short hairpin RNA silencing. Conclusions Set7 regulates the phenotypic endothelial-mesenchymal transition switch and suggests that targeting the lysine methyltransferase could protect glomerular cell injury in DKD. {\textcopyright} 2024 Wolters Kluwer Health. All rights reserved.",

keywords = "diabetes, diabetes mellitus, diabetic kidney disease, diabetic nephropathy, endothelium, gene expression, gene transcription",

author = "Scott Maxwell and Jun Okabe and Harikrishnan Kaipananickal and Hanah Rodriguez and Ishant Khurana and Keith Al-Hasani and Chow, \{Bryna S.M.\} and Eleni Pitsillou and Karagiannis, \{Tom C.\} and Karin Jandeleit-Dahm and Ma, \{Ronald C.W.\} and Yu Huang and Chan, \{Juliana C.N.\} and Cooper, \{Mark E.\} and Assam El-Osta",

year = "2024",

month = jun,

doi = "10.1681/ASN.0000000000000345",

language = "English",

volume = "35",

pages = "733--748",

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Maxwell, S, Okabe, J, Kaipananickal, H, Rodriguez, H, Khurana, I, Al-Hasani, K, Chow, BSM, Pitsillou, E, Karagiannis, TC, Jandeleit-Dahm, K, Ma, RCW, Huang, Y, Chan, JCN, Cooper, ME & El-Osta, A 2024, 'Set7 Methyltransferase and Phenotypic Switch in Diabetic Glomerular Endothelial Cells', Journal of the American Society of Nephrology, vol. 35, no. 6, pp. 733-748. https://doi.org/10.1681/ASN.0000000000000345

TY - JOUR

T1 - Set7 Methyltransferase and Phenotypic Switch in Diabetic Glomerular Endothelial Cells

AU - Maxwell, Scott

AU - Okabe, Jun

AU - Kaipananickal, Harikrishnan

AU - Rodriguez, Hanah

AU - Khurana, Ishant

AU - Al-Hasani, Keith

AU - Chow, Bryna S.M.

AU - Pitsillou, Eleni

AU - Karagiannis, Tom C.

AU - Jandeleit-Dahm, Karin

AU - Ma, Ronald C.W.

AU - Huang, Yu

AU - Chan, Juliana C.N.

AU - Cooper, Mark E.

AU - El-Osta, Assam

PY - 2024/6

Y1 - 2024/6

N2 - Background Hyperglycemia influences the development of glomerular endothelial cell damage, and nowhere is this more evident than in the progression of diabetic kidney disease (DKD). While the Set7 lysine methyltransferase is a known hyperglycemic sensor, its role in endothelial cell function in the context of DKD remains poorly understood. Methods Single-cell transcriptomics was used to investigate Set7 regulation in a mouse model of DKD, followed by validation of findings using pharmacological and short hairpin RNA inhibition inhibition of Set7. Results Set7 knockout (Set7KO) improved glomerular structure and albuminuria in a mouse model of diabetes. Analysis of single-cell RNA-sequencing data showed dynamic transcriptional changes in diabetic renal cells. Set7KO controls phenotype switching of glomerular endothelial cell populations by transcriptional regulation of the insulin growth factor binding protein 5 (IGFBP5). Chromatin immunoprecipitation assays confirmed that the expression of the IGFBP5 gene was associated with mono- and dimethylation of histone H3 lysine 4 (H3K4me1/2). This generalizability was investigated in human kidney and circulating hyperglycemic cells exposed to TGFβ1. We showed that the highly selective Set7 inhibitor (R)-PFI-2 hydrochloride attenuated indices associated with renal cell damage and mesenchymal transition, specifically (1) reactive oxygen species production, (2) IGFBP5 gene regulation, and (3) expression of mesenchymal markers. Furthermore, renal benefit observed in Set7KO diabetic mice closely corresponded in human glomerular endothelial cells with (R)-PFI-2 hydrochloride inhibition or Set7 short hairpin RNA silencing. Conclusions Set7 regulates the phenotypic endothelial-mesenchymal transition switch and suggests that targeting the lysine methyltransferase could protect glomerular cell injury in DKD. © 2024 Wolters Kluwer Health. All rights reserved.

AB - Background Hyperglycemia influences the development of glomerular endothelial cell damage, and nowhere is this more evident than in the progression of diabetic kidney disease (DKD). While the Set7 lysine methyltransferase is a known hyperglycemic sensor, its role in endothelial cell function in the context of DKD remains poorly understood. Methods Single-cell transcriptomics was used to investigate Set7 regulation in a mouse model of DKD, followed by validation of findings using pharmacological and short hairpin RNA inhibition inhibition of Set7. Results Set7 knockout (Set7KO) improved glomerular structure and albuminuria in a mouse model of diabetes. Analysis of single-cell RNA-sequencing data showed dynamic transcriptional changes in diabetic renal cells. Set7KO controls phenotype switching of glomerular endothelial cell populations by transcriptional regulation of the insulin growth factor binding protein 5 (IGFBP5). Chromatin immunoprecipitation assays confirmed that the expression of the IGFBP5 gene was associated with mono- and dimethylation of histone H3 lysine 4 (H3K4me1/2). This generalizability was investigated in human kidney and circulating hyperglycemic cells exposed to TGFβ1. We showed that the highly selective Set7 inhibitor (R)-PFI-2 hydrochloride attenuated indices associated with renal cell damage and mesenchymal transition, specifically (1) reactive oxygen species production, (2) IGFBP5 gene regulation, and (3) expression of mesenchymal markers. Furthermore, renal benefit observed in Set7KO diabetic mice closely corresponded in human glomerular endothelial cells with (R)-PFI-2 hydrochloride inhibition or Set7 short hairpin RNA silencing. Conclusions Set7 regulates the phenotypic endothelial-mesenchymal transition switch and suggests that targeting the lysine methyltransferase could protect glomerular cell injury in DKD. © 2024 Wolters Kluwer Health. All rights reserved.

KW - diabetes

KW - diabetes mellitus

KW - diabetic kidney disease

KW - diabetic nephropathy

KW - endothelium

KW - gene expression

KW - gene transcription

UR - https://www.scopus.com/pages/publications/85195417423

UR - https://www.scopus.com/pages/publications/85195417423#tab=impact

U2 - 10.1681/ASN.0000000000000345

DO - 10.1681/ASN.0000000000000345

M3 - RGC 21 - Publication in refereed journal

C2 - 38630537

SN - 1046-6673

VL - 35

SP - 733

EP - 748

JO - Journal of the American Society of Nephrology

JF - Journal of the American Society of Nephrology

IS - 6

ER -

Set7 Methyltransferase and Phenotypic Switch in Diabetic Glomerular Endothelial Cells

Abstract

Funding

UN SDGs

Research Keywords

Publisher's Copyright Statement

RGC Funding Information

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SRFS: Systemic Benefits of Physical Activity: Crosstalk between Organs on Signal Transduction from Mechano-stimulation to Metabolism

Cite this

Set7 Methyltransferase and Phenotypic Switch in Diabetic Glomerular Endothelial Cells

Abstract

Funding

UN SDGs

Research Keywords

Publisher's Copyright Statement

RGC Funding Information

Access Output

Other Access Options

Permanent Link

Other Files and Links

Fingerprint

Projects

SRFS: Systemic Benefits of Physical Activity: Crosstalk between Organs on Signal Transduction from Mechano-stimulation to Metabolism

Cite this