Modification of the transcriptomic response to renal ischemia/reperfusion injury by lipoxin analog

Niamh E. Kieran, Peter P. Doran, Susan B. Connolly, Marie Claire Greenan, Debra F. Higgins, Martin Leonard, Catherine Godson, Cormac T. Taylor, Anna Henger, Matthias Kretzler, Melissa J. Burne, Hamid Rabb, Hugh R. Brady

Research output: Contribution to journalArticle

Abstract

Background. Lipoxins are lipoxygenase-derived eicosanoids with anti-inflammatory and proresolution bioactivities in vitro and in vivo. We have previously demonstrated that the stable synthetic LXA4 analog 15-epi-16-(FPhO)-LXA4-Me is renoprotective in murine renal ischemia/reperfusion injury, as gauged by lower serum creatinine, attenuated leukocyte infiltration, and reduced morphologic tubule injury. Methods. We employed complementary oligonucleotide microarray and bioinformatic analyses to probe the transcriptomic events that underpin lipoxin renoprotection in this setting. Results. Microarray-based analysis identified three broad categories of genes whose mRNA levels are altered in response to ischemia/reperfusion injury, including known genes previously implicated in the pathogenesis of ischemia/reperfusion injury [e.g., intercellular adhesion molecule-1 (ICAM-1), p21, KIM-1], known genes not previously associated with ischemia/reperfusion injury, and cDNAs representing yet uncharacterized genes. Characterization of expressed sequence tags (ESTs) displayed on microarrays represents a major challenge in studies of global gene expression. A bioinformatic annotation pipeline successfully annotated a large proportion of ESTs modulated during ischemia/reperfusion injury. The differential expression of a representative group of these ischemia/reperfusion injury-modulated genes was confirmed by real-time polymerase chain reaction. Prominent among the up-regulated genes were claudin-1, -3, and -7, and ADAM8. Interestingly, the former response was claudin-specific and was not observed with other claudins expressed by the kidney (e.g., claudin-8 and -6) or indeed with other components of the renal tight junctions (e.g., occludin and junctional adhesion molecule). Noteworthy among the down-regulated genes was a cluster of transport proteins (e.g., aquaporin-1) and the zinc metalloendopeptidase meprin-1β implicated in renal remodeling. Conclusion. Treatment with the lipoxin analog 15-epi-16-(FPhO)-LXA4-Me prior to injury modified the expression of many differentially expressed pathogenic mediators, including cytokines, growth factors, adhesion molecules, and proteases, suggesting a renoprotective action at the core of the pathophysiology of acute renal failure (ARF). Importantly, this lipoxin-modulated transcriptomic response included many genes expressed by renal parenchymal cells and was not merely a reflection of a reduced renal mRNA load resulting from attenuated leukocyte recruitment. The data presented herein suggest a framework for understanding drivers of kidney injury in ischemia/reperfusion and the molecular basis for renoprotection by lipoxins in this setting.

Original languageEnglish (US)
Pages (from-to)480-492
Number of pages13
JournalKidney International
Volume64
Issue number2
DOIs
StatePublished - Aug 1 2003
Externally publishedYes

Fingerprint

Lipoxins
Reperfusion Injury
Kidney
Genes
Junctional Adhesion Molecules
Expressed Sequence Tags
Microarray Analysis
Computational Biology
Claudin-3
Leukocytes
Metalloendopeptidases
Tiopronin
Claudins
Claudin-1
Aquaporin 1
Occludin
Messenger RNA
Lipoxygenase
Eicosanoids
Tight Junctions

Keywords

  • Acute renal failure
  • ADAM8
  • Bioinformatics
  • Claudins
  • Gene chips
  • Ischemia
  • Lipoxins
  • Meprin
  • Microarrays

ASJC Scopus subject areas

  • Nephrology

Cite this

Kieran, N. E., Doran, P. P., Connolly, S. B., Greenan, M. C., Higgins, D. F., Leonard, M., ... Brady, H. R. (2003). Modification of the transcriptomic response to renal ischemia/reperfusion injury by lipoxin analog. Kidney International, 64(2), 480-492. https://doi.org/10.1046/j.1523-1755.2003.00106.x

Modification of the transcriptomic response to renal ischemia/reperfusion injury by lipoxin analog. / Kieran, Niamh E.; Doran, Peter P.; Connolly, Susan B.; Greenan, Marie Claire; Higgins, Debra F.; Leonard, Martin; Godson, Catherine; Taylor, Cormac T.; Henger, Anna; Kretzler, Matthias; Burne, Melissa J.; Rabb, Hamid; Brady, Hugh R.

In: Kidney International, Vol. 64, No. 2, 01.08.2003, p. 480-492.

Research output: Contribution to journalArticle

Kieran, NE, Doran, PP, Connolly, SB, Greenan, MC, Higgins, DF, Leonard, M, Godson, C, Taylor, CT, Henger, A, Kretzler, M, Burne, MJ, Rabb, H & Brady, HR 2003, 'Modification of the transcriptomic response to renal ischemia/reperfusion injury by lipoxin analog', Kidney International, vol. 64, no. 2, pp. 480-492. https://doi.org/10.1046/j.1523-1755.2003.00106.x
Kieran, Niamh E. ; Doran, Peter P. ; Connolly, Susan B. ; Greenan, Marie Claire ; Higgins, Debra F. ; Leonard, Martin ; Godson, Catherine ; Taylor, Cormac T. ; Henger, Anna ; Kretzler, Matthias ; Burne, Melissa J. ; Rabb, Hamid ; Brady, Hugh R. / Modification of the transcriptomic response to renal ischemia/reperfusion injury by lipoxin analog. In: Kidney International. 2003 ; Vol. 64, No. 2. pp. 480-492.
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T1 - Modification of the transcriptomic response to renal ischemia/reperfusion injury by lipoxin analog

AU - Kieran, Niamh E.

AU - Doran, Peter P.

AU - Connolly, Susan B.

AU - Greenan, Marie Claire

AU - Higgins, Debra F.

AU - Leonard, Martin

AU - Godson, Catherine

AU - Taylor, Cormac T.

AU - Henger, Anna

AU - Kretzler, Matthias

AU - Burne, Melissa J.

AU - Rabb, Hamid

AU - Brady, Hugh R.

PY - 2003/8/1

Y1 - 2003/8/1

N2 - Background. Lipoxins are lipoxygenase-derived eicosanoids with anti-inflammatory and proresolution bioactivities in vitro and in vivo. We have previously demonstrated that the stable synthetic LXA4 analog 15-epi-16-(FPhO)-LXA4-Me is renoprotective in murine renal ischemia/reperfusion injury, as gauged by lower serum creatinine, attenuated leukocyte infiltration, and reduced morphologic tubule injury. Methods. We employed complementary oligonucleotide microarray and bioinformatic analyses to probe the transcriptomic events that underpin lipoxin renoprotection in this setting. Results. Microarray-based analysis identified three broad categories of genes whose mRNA levels are altered in response to ischemia/reperfusion injury, including known genes previously implicated in the pathogenesis of ischemia/reperfusion injury [e.g., intercellular adhesion molecule-1 (ICAM-1), p21, KIM-1], known genes not previously associated with ischemia/reperfusion injury, and cDNAs representing yet uncharacterized genes. Characterization of expressed sequence tags (ESTs) displayed on microarrays represents a major challenge in studies of global gene expression. A bioinformatic annotation pipeline successfully annotated a large proportion of ESTs modulated during ischemia/reperfusion injury. The differential expression of a representative group of these ischemia/reperfusion injury-modulated genes was confirmed by real-time polymerase chain reaction. Prominent among the up-regulated genes were claudin-1, -3, and -7, and ADAM8. Interestingly, the former response was claudin-specific and was not observed with other claudins expressed by the kidney (e.g., claudin-8 and -6) or indeed with other components of the renal tight junctions (e.g., occludin and junctional adhesion molecule). Noteworthy among the down-regulated genes was a cluster of transport proteins (e.g., aquaporin-1) and the zinc metalloendopeptidase meprin-1β implicated in renal remodeling. Conclusion. Treatment with the lipoxin analog 15-epi-16-(FPhO)-LXA4-Me prior to injury modified the expression of many differentially expressed pathogenic mediators, including cytokines, growth factors, adhesion molecules, and proteases, suggesting a renoprotective action at the core of the pathophysiology of acute renal failure (ARF). Importantly, this lipoxin-modulated transcriptomic response included many genes expressed by renal parenchymal cells and was not merely a reflection of a reduced renal mRNA load resulting from attenuated leukocyte recruitment. The data presented herein suggest a framework for understanding drivers of kidney injury in ischemia/reperfusion and the molecular basis for renoprotection by lipoxins in this setting.

AB - Background. Lipoxins are lipoxygenase-derived eicosanoids with anti-inflammatory and proresolution bioactivities in vitro and in vivo. We have previously demonstrated that the stable synthetic LXA4 analog 15-epi-16-(FPhO)-LXA4-Me is renoprotective in murine renal ischemia/reperfusion injury, as gauged by lower serum creatinine, attenuated leukocyte infiltration, and reduced morphologic tubule injury. Methods. We employed complementary oligonucleotide microarray and bioinformatic analyses to probe the transcriptomic events that underpin lipoxin renoprotection in this setting. Results. Microarray-based analysis identified three broad categories of genes whose mRNA levels are altered in response to ischemia/reperfusion injury, including known genes previously implicated in the pathogenesis of ischemia/reperfusion injury [e.g., intercellular adhesion molecule-1 (ICAM-1), p21, KIM-1], known genes not previously associated with ischemia/reperfusion injury, and cDNAs representing yet uncharacterized genes. Characterization of expressed sequence tags (ESTs) displayed on microarrays represents a major challenge in studies of global gene expression. A bioinformatic annotation pipeline successfully annotated a large proportion of ESTs modulated during ischemia/reperfusion injury. The differential expression of a representative group of these ischemia/reperfusion injury-modulated genes was confirmed by real-time polymerase chain reaction. Prominent among the up-regulated genes were claudin-1, -3, and -7, and ADAM8. Interestingly, the former response was claudin-specific and was not observed with other claudins expressed by the kidney (e.g., claudin-8 and -6) or indeed with other components of the renal tight junctions (e.g., occludin and junctional adhesion molecule). Noteworthy among the down-regulated genes was a cluster of transport proteins (e.g., aquaporin-1) and the zinc metalloendopeptidase meprin-1β implicated in renal remodeling. Conclusion. Treatment with the lipoxin analog 15-epi-16-(FPhO)-LXA4-Me prior to injury modified the expression of many differentially expressed pathogenic mediators, including cytokines, growth factors, adhesion molecules, and proteases, suggesting a renoprotective action at the core of the pathophysiology of acute renal failure (ARF). Importantly, this lipoxin-modulated transcriptomic response included many genes expressed by renal parenchymal cells and was not merely a reflection of a reduced renal mRNA load resulting from attenuated leukocyte recruitment. The data presented herein suggest a framework for understanding drivers of kidney injury in ischemia/reperfusion and the molecular basis for renoprotection by lipoxins in this setting.

KW - Acute renal failure

KW - ADAM8

KW - Bioinformatics

KW - Claudins

KW - Gene chips

KW - Ischemia

KW - Lipoxins

KW - Meprin

KW - Microarrays

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