RAGE deletion confers renoprotection by reducing responsiveness to transforming growth factor-β and increasing resistance to apoptosis

Shinji Hagiwara, Karly Sourris, Mark Ziemann, Wu Tieqiao, Muthukumar Mohan, Aaron D. McClelland, Eoin Brennan, Josephine Forbes, Melinda Coughlan, Brooke Harcourt, Sally Penfold, Bo Wang, Gavin Higgins, Raelene Pickering, Assam El-Osta, Merlin C. Thomas, Mark E. Cooper, Phillip Kantharidis

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Signaling via the receptor of advanced glycation end products (RAGE)-though complex and not fully elucidated in the setting of diabetes-is considered a key injurious pathway in the development of diabetic nephropathy (DN). We report here that RAGE deletion resulted in increased expression of fibrotic markers (collagen I and IV, fibronectin) and the inflammatory marker MCP-1 in primary mouse mesangial cells (MCs) and in kidney cortex. RNA sequencing analysis in MCs from RAGE-/- and wild-type mice confirmed these observations. Nevertheless, despite these gene expression changes, decreased responsiveness to transforming growth factor-β was identified in RAGE-/- mice. Furthermore, RAGE deletion conferred a more proliferative phenotype in MCs and reduced susceptibility to staurosporine-induced apoptosis. RAGE restoration experiments in RAGE-/- MCs largely reversed these gene expression changes, resulting in reduced expression of fibrotic and inflammatory markers. This study highlights that protection against DN in RAGE knockout mice is likely to be due in part to the decreased responsiveness to growth factor stimulation and an antiapoptotic phenotype in MCs. Furthermore, it extends our understanding of the role of RAGE in the progression of DN, as RAGE seems to play a key role in modulating the sensitivity of the kidney to injurious stimuli such as prosclerotic cytokines.

Original languageEnglish
Pages (from-to)960-973
Number of pages14
JournalDiabetes
Volume67
Issue number5
DOIs
Publication statusPublished - 1 May 2018

Cite this

Hagiwara, Shinji ; Sourris, Karly ; Ziemann, Mark ; Tieqiao, Wu ; Mohan, Muthukumar ; McClelland, Aaron D. ; Brennan, Eoin ; Forbes, Josephine ; Coughlan, Melinda ; Harcourt, Brooke ; Penfold, Sally ; Wang, Bo ; Higgins, Gavin ; Pickering, Raelene ; El-Osta, Assam ; Thomas, Merlin C. ; Cooper, Mark E. ; Kantharidis, Phillip. / RAGE deletion confers renoprotection by reducing responsiveness to transforming growth factor-β and increasing resistance to apoptosis. In: Diabetes. 2018 ; Vol. 67, No. 5. pp. 960-973.
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abstract = "Signaling via the receptor of advanced glycation end products (RAGE)-though complex and not fully elucidated in the setting of diabetes-is considered a key injurious pathway in the development of diabetic nephropathy (DN). We report here that RAGE deletion resulted in increased expression of fibrotic markers (collagen I and IV, fibronectin) and the inflammatory marker MCP-1 in primary mouse mesangial cells (MCs) and in kidney cortex. RNA sequencing analysis in MCs from RAGE-/- and wild-type mice confirmed these observations. Nevertheless, despite these gene expression changes, decreased responsiveness to transforming growth factor-β was identified in RAGE-/- mice. Furthermore, RAGE deletion conferred a more proliferative phenotype in MCs and reduced susceptibility to staurosporine-induced apoptosis. RAGE restoration experiments in RAGE-/- MCs largely reversed these gene expression changes, resulting in reduced expression of fibrotic and inflammatory markers. This study highlights that protection against DN in RAGE knockout mice is likely to be due in part to the decreased responsiveness to growth factor stimulation and an antiapoptotic phenotype in MCs. Furthermore, it extends our understanding of the role of RAGE in the progression of DN, as RAGE seems to play a key role in modulating the sensitivity of the kidney to injurious stimuli such as prosclerotic cytokines.",
author = "Shinji Hagiwara and Karly Sourris and Mark Ziemann and Wu Tieqiao and Muthukumar Mohan and McClelland, {Aaron D.} and Eoin Brennan and Josephine Forbes and Melinda Coughlan and Brooke Harcourt and Sally Penfold and Bo Wang and Gavin Higgins and Raelene Pickering and Assam El-Osta and Thomas, {Merlin C.} and Cooper, {Mark E.} and Phillip Kantharidis",
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RAGE deletion confers renoprotection by reducing responsiveness to transforming growth factor-β and increasing resistance to apoptosis. / Hagiwara, Shinji; Sourris, Karly; Ziemann, Mark; Tieqiao, Wu; Mohan, Muthukumar; McClelland, Aaron D.; Brennan, Eoin; Forbes, Josephine; Coughlan, Melinda; Harcourt, Brooke; Penfold, Sally; Wang, Bo; Higgins, Gavin; Pickering, Raelene; El-Osta, Assam; Thomas, Merlin C.; Cooper, Mark E.; Kantharidis, Phillip.

In: Diabetes, Vol. 67, No. 5, 01.05.2018, p. 960-973.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Hagiwara, Shinji

AU - Sourris, Karly

AU - Ziemann, Mark

AU - Tieqiao, Wu

AU - Mohan, Muthukumar

AU - McClelland, Aaron D.

AU - Brennan, Eoin

AU - Forbes, Josephine

AU - Coughlan, Melinda

AU - Harcourt, Brooke

AU - Penfold, Sally

AU - Wang, Bo

AU - Higgins, Gavin

AU - Pickering, Raelene

AU - El-Osta, Assam

AU - Thomas, Merlin C.

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AU - Kantharidis, Phillip

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N2 - Signaling via the receptor of advanced glycation end products (RAGE)-though complex and not fully elucidated in the setting of diabetes-is considered a key injurious pathway in the development of diabetic nephropathy (DN). We report here that RAGE deletion resulted in increased expression of fibrotic markers (collagen I and IV, fibronectin) and the inflammatory marker MCP-1 in primary mouse mesangial cells (MCs) and in kidney cortex. RNA sequencing analysis in MCs from RAGE-/- and wild-type mice confirmed these observations. Nevertheless, despite these gene expression changes, decreased responsiveness to transforming growth factor-β was identified in RAGE-/- mice. Furthermore, RAGE deletion conferred a more proliferative phenotype in MCs and reduced susceptibility to staurosporine-induced apoptosis. RAGE restoration experiments in RAGE-/- MCs largely reversed these gene expression changes, resulting in reduced expression of fibrotic and inflammatory markers. This study highlights that protection against DN in RAGE knockout mice is likely to be due in part to the decreased responsiveness to growth factor stimulation and an antiapoptotic phenotype in MCs. Furthermore, it extends our understanding of the role of RAGE in the progression of DN, as RAGE seems to play a key role in modulating the sensitivity of the kidney to injurious stimuli such as prosclerotic cytokines.

AB - Signaling via the receptor of advanced glycation end products (RAGE)-though complex and not fully elucidated in the setting of diabetes-is considered a key injurious pathway in the development of diabetic nephropathy (DN). We report here that RAGE deletion resulted in increased expression of fibrotic markers (collagen I and IV, fibronectin) and the inflammatory marker MCP-1 in primary mouse mesangial cells (MCs) and in kidney cortex. RNA sequencing analysis in MCs from RAGE-/- and wild-type mice confirmed these observations. Nevertheless, despite these gene expression changes, decreased responsiveness to transforming growth factor-β was identified in RAGE-/- mice. Furthermore, RAGE deletion conferred a more proliferative phenotype in MCs and reduced susceptibility to staurosporine-induced apoptosis. RAGE restoration experiments in RAGE-/- MCs largely reversed these gene expression changes, resulting in reduced expression of fibrotic and inflammatory markers. This study highlights that protection against DN in RAGE knockout mice is likely to be due in part to the decreased responsiveness to growth factor stimulation and an antiapoptotic phenotype in MCs. Furthermore, it extends our understanding of the role of RAGE in the progression of DN, as RAGE seems to play a key role in modulating the sensitivity of the kidney to injurious stimuli such as prosclerotic cytokines.

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