Lipoxins regulate the early growth response-1 network and reverse diabetic kidney disease

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

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Background The failure of spontaneous resolution underlies chronic inflammatory conditions, including microvascular complications of diabetes such as diabetic kidney disease. The identification of endogenously generated molecules that promote the physiologic resolution of inflammation suggests that these bioactions may have therapeutic potential in the context of chronic inflammation. Lipoxins (LXs) are lipid mediators that promote the resolution of inflammation. Methods We investigated the potential of LXA4 and a synthetic LX analog (Benzo-LXA4) as therapeutics in a murine model of diabetic kidney disease, ApoE-/- mice treated with streptozotocin. Results Intraperitoneal injection of LXs attenuated the development of diabetes-induced albuminuria, mesangial expansion, and collagen deposition. Notably, LXs administered 10weeks after disease onset also attenuated established kidney disease, with evidence of preserved kidney function. Kidney transcriptome profiling defined a diabetic signature (725 genes; false discovery rate P ≤0.05). Comparison of this murine gene signature with that of human diabetic kidney disease identified shared renalproinflammatory/profibrotic signals (TNF-α, IL-1β,NF-κB). Indiabetic mice, we identified 20 and 51 transcripts regulated by LXA4 and Benzo-LXA4, respectively, and pathway analysis identified established (TGF-β1, PDGF, TNF-α, NF-κB) and novel (early growth response-1 [EGR-1]) networks activatedindiabetes andregulatedby LXs. Inculturedhuman renal epithelial cells, treatment with LXs attenuated TNF-α-driven Egr-1 activation, and Egr-1 depletion prevented cellular responses to TGF-β1 and TNF-α. Conclusions These data demonstrate that LXs can reverse established diabetic complications and support a therapeutic paradigm to promote the resolution of inflammation.

Original languageEnglish
Pages (from-to)1437-1448
Number of pages12
JournalJournal of the American Society of Nephrology
Volume29
Issue number5
DOIs
Publication statusPublished - 1 May 2018

Cite this

Brennan, Eoin P. ; Mohan, Muthukumar ; McClelland, Aaron ; Tikellis, Christos ; Ziemann, Mark ; Kaspi, Antony ; Gray, Stephen P. ; Pickering, Raelene ; Tan, Sih Min ; Tasadaque Ali-Shah, Syed ; Guiry, Patrick J. ; El-Osta, Assam ; Jandeleit-Dahm, Karin ; Cooper, Mark E. ; Godson, Catherine ; Kantharidis, Phillip. / Lipoxins regulate the early growth response-1 network and reverse diabetic kidney disease. In: Journal of the American Society of Nephrology. 2018 ; Vol. 29, No. 5. pp. 1437-1448.
@article{340b047b12bb43a1a79c0bc530112dfd,
title = "Lipoxins regulate the early growth response-1 network and reverse diabetic kidney disease",
abstract = "Background The failure of spontaneous resolution underlies chronic inflammatory conditions, including microvascular complications of diabetes such as diabetic kidney disease. The identification of endogenously generated molecules that promote the physiologic resolution of inflammation suggests that these bioactions may have therapeutic potential in the context of chronic inflammation. Lipoxins (LXs) are lipid mediators that promote the resolution of inflammation. Methods We investigated the potential of LXA4 and a synthetic LX analog (Benzo-LXA4) as therapeutics in a murine model of diabetic kidney disease, ApoE-/- mice treated with streptozotocin. Results Intraperitoneal injection of LXs attenuated the development of diabetes-induced albuminuria, mesangial expansion, and collagen deposition. Notably, LXs administered 10weeks after disease onset also attenuated established kidney disease, with evidence of preserved kidney function. Kidney transcriptome profiling defined a diabetic signature (725 genes; false discovery rate P ≤0.05). Comparison of this murine gene signature with that of human diabetic kidney disease identified shared renalproinflammatory/profibrotic signals (TNF-α, IL-1β,NF-κB). Indiabetic mice, we identified 20 and 51 transcripts regulated by LXA4 and Benzo-LXA4, respectively, and pathway analysis identified established (TGF-β1, PDGF, TNF-α, NF-κB) and novel (early growth response-1 [EGR-1]) networks activatedindiabetes andregulatedby LXs. Inculturedhuman renal epithelial cells, treatment with LXs attenuated TNF-α-driven Egr-1 activation, and Egr-1 depletion prevented cellular responses to TGF-β1 and TNF-α. Conclusions These data demonstrate that LXs can reverse established diabetic complications and support a therapeutic paradigm to promote the resolution of inflammation.",
author = "Brennan, {Eoin P.} and Muthukumar Mohan and Aaron McClelland and Christos Tikellis and Mark Ziemann and Antony Kaspi and Gray, {Stephen P.} and Raelene Pickering and Tan, {Sih Min} and {Tasadaque Ali-Shah}, Syed and Guiry, {Patrick J.} and Assam El-Osta and Karin Jandeleit-Dahm and Cooper, {Mark E.} and Catherine Godson and Phillip Kantharidis",
year = "2018",
month = "5",
day = "1",
doi = "10.1681/ASN.2017101112",
language = "English",
volume = "29",
pages = "1437--1448",
journal = "Journal of the American Society of Nephrology",
issn = "1046-6673",
publisher = "American Society of Nephrology",
number = "5",

}

Lipoxins regulate the early growth response-1 network and reverse diabetic kidney disease. / Brennan, Eoin P.; Mohan, Muthukumar; McClelland, Aaron; Tikellis, Christos; Ziemann, Mark; Kaspi, Antony; Gray, Stephen P.; Pickering, Raelene; Tan, Sih Min; Tasadaque Ali-Shah, Syed; Guiry, Patrick J.; El-Osta, Assam; Jandeleit-Dahm, Karin; Cooper, Mark E.; Godson, Catherine; Kantharidis, Phillip.

In: Journal of the American Society of Nephrology, Vol. 29, No. 5, 01.05.2018, p. 1437-1448.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Lipoxins regulate the early growth response-1 network and reverse diabetic kidney disease

AU - Brennan, Eoin P.

AU - Mohan, Muthukumar

AU - McClelland, Aaron

AU - Tikellis, Christos

AU - Ziemann, Mark

AU - Kaspi, Antony

AU - Gray, Stephen P.

AU - Pickering, Raelene

AU - Tan, Sih Min

AU - Tasadaque Ali-Shah, Syed

AU - Guiry, Patrick J.

AU - El-Osta, Assam

AU - Jandeleit-Dahm, Karin

AU - Cooper, Mark E.

AU - Godson, Catherine

AU - Kantharidis, Phillip

PY - 2018/5/1

Y1 - 2018/5/1

N2 - Background The failure of spontaneous resolution underlies chronic inflammatory conditions, including microvascular complications of diabetes such as diabetic kidney disease. The identification of endogenously generated molecules that promote the physiologic resolution of inflammation suggests that these bioactions may have therapeutic potential in the context of chronic inflammation. Lipoxins (LXs) are lipid mediators that promote the resolution of inflammation. Methods We investigated the potential of LXA4 and a synthetic LX analog (Benzo-LXA4) as therapeutics in a murine model of diabetic kidney disease, ApoE-/- mice treated with streptozotocin. Results Intraperitoneal injection of LXs attenuated the development of diabetes-induced albuminuria, mesangial expansion, and collagen deposition. Notably, LXs administered 10weeks after disease onset also attenuated established kidney disease, with evidence of preserved kidney function. Kidney transcriptome profiling defined a diabetic signature (725 genes; false discovery rate P ≤0.05). Comparison of this murine gene signature with that of human diabetic kidney disease identified shared renalproinflammatory/profibrotic signals (TNF-α, IL-1β,NF-κB). Indiabetic mice, we identified 20 and 51 transcripts regulated by LXA4 and Benzo-LXA4, respectively, and pathway analysis identified established (TGF-β1, PDGF, TNF-α, NF-κB) and novel (early growth response-1 [EGR-1]) networks activatedindiabetes andregulatedby LXs. Inculturedhuman renal epithelial cells, treatment with LXs attenuated TNF-α-driven Egr-1 activation, and Egr-1 depletion prevented cellular responses to TGF-β1 and TNF-α. Conclusions These data demonstrate that LXs can reverse established diabetic complications and support a therapeutic paradigm to promote the resolution of inflammation.

AB - Background The failure of spontaneous resolution underlies chronic inflammatory conditions, including microvascular complications of diabetes such as diabetic kidney disease. The identification of endogenously generated molecules that promote the physiologic resolution of inflammation suggests that these bioactions may have therapeutic potential in the context of chronic inflammation. Lipoxins (LXs) are lipid mediators that promote the resolution of inflammation. Methods We investigated the potential of LXA4 and a synthetic LX analog (Benzo-LXA4) as therapeutics in a murine model of diabetic kidney disease, ApoE-/- mice treated with streptozotocin. Results Intraperitoneal injection of LXs attenuated the development of diabetes-induced albuminuria, mesangial expansion, and collagen deposition. Notably, LXs administered 10weeks after disease onset also attenuated established kidney disease, with evidence of preserved kidney function. Kidney transcriptome profiling defined a diabetic signature (725 genes; false discovery rate P ≤0.05). Comparison of this murine gene signature with that of human diabetic kidney disease identified shared renalproinflammatory/profibrotic signals (TNF-α, IL-1β,NF-κB). Indiabetic mice, we identified 20 and 51 transcripts regulated by LXA4 and Benzo-LXA4, respectively, and pathway analysis identified established (TGF-β1, PDGF, TNF-α, NF-κB) and novel (early growth response-1 [EGR-1]) networks activatedindiabetes andregulatedby LXs. Inculturedhuman renal epithelial cells, treatment with LXs attenuated TNF-α-driven Egr-1 activation, and Egr-1 depletion prevented cellular responses to TGF-β1 and TNF-α. Conclusions These data demonstrate that LXs can reverse established diabetic complications and support a therapeutic paradigm to promote the resolution of inflammation.

UR - http://www.scopus.com/inward/record.url?scp=85046351735&partnerID=8YFLogxK

U2 - 10.1681/ASN.2017101112

DO - 10.1681/ASN.2017101112

M3 - Article

VL - 29

SP - 1437

EP - 1448

JO - Journal of the American Society of Nephrology

JF - Journal of the American Society of Nephrology

SN - 1046-6673

IS - 5

ER -