Transcriptome analysis of renal ischemia/reperfusion injury and its modulation by ischemic pre-conditioning or hemin treatment

PLoS One. 2012;7(11):e49569. doi: 10.1371/journal.pone.0049569. Epub 2012 Nov 14.

Abstract

Ischemia/reperfusion injury (IRI) is a leading cause of acute renal failure. The definition of the molecular mechanisms involved in renal IRI and counter protection promoted by ischemic pre-conditioning (IPC) or Hemin treatment is an important milestone that needs to be accomplished in this research area. We examined, through an oligonucleotide microarray protocol, the renal differential transcriptome profiles of mice submitted to IRI, IPC and Hemin treatment. After identifying the profiles of differentially expressed genes observed for each comparison, we carried out functional enrichment analysis to reveal transcripts putatively involved in potential relevant biological processes and signaling pathways. The most relevant processes found in these comparisons were stress, apoptosis, cell differentiation, angiogenesis, focal adhesion, ECM-receptor interaction, ion transport, angiogenesis, mitosis and cell cycle, inflammatory response, olfactory transduction and regulation of actin cytoskeleton. In addition, the most important overrepresented pathways were MAPK, ErbB, JAK/STAT, Toll and Nod like receptors, Angiotensin II, Arachidonic acid metabolism, Wnt and coagulation cascade. Also, new insights were gained about the underlying protection mechanisms against renal IRI promoted by IPC and Hemin treatment. Venn diagram analysis allowed us to uncover common and exclusively differentially expressed genes between these two protective maneuvers, underscoring potential common and exclusive biological functions regulated in each case. In summary, IPC exclusively regulated the expression of genes belonging to stress, protein modification and apoptosis, highlighting the role of IPC in controlling exacerbated stress response. Treatment with the Hmox1 inducer Hemin, in turn, exclusively regulated the expression of genes associated with cell differentiation, metabolic pathways, cell cycle, mitosis, development, regulation of actin cytoskeleton and arachidonic acid metabolism, suggesting a pleiotropic effect for Hemin. These findings improve the biological understanding of how the kidney behaves after IRI. They also illustrate some possible underlying molecular mechanisms involved in kidney protection observed with IPC or Hemin treatment maneuvers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury / drug therapy
  • Acute Kidney Injury / genetics*
  • Acute Kidney Injury / metabolism
  • Animals
  • Gene Expression Profiling*
  • Gene Expression Regulation / drug effects
  • Hemin / administration & dosage
  • Hemin / pharmacology*
  • Ischemic Preconditioning*
  • Kidney / blood supply*
  • Male
  • Mice
  • Reperfusion Injury / drug therapy
  • Reperfusion Injury / genetics*
  • Reperfusion Injury / metabolism
  • Reproducibility of Results
  • Signal Transduction

Substances

  • Hemin

Grant support

This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo-FAPESP (2007/07139-3, 2009/54474-8 and 2012/02270-2) and Conselho Nacional de Desenvolvimento Cientifico e Tecnológico - CNPq/International Associated Laboratory in Renal Physiopathology (CNPq/Inserm) and Complex Fluids INCT (CNPq/FAPESP). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.