Ischemic and nephrotoxic acute renal failure are distinguished by their broad transcriptomic responses

Peter S.T. Yuen, Sang Kyung Jo, Mikaela K. Holly, Xuzhen Hu, Robert A. Star

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

Acute renal failure (ARF) has a high morbidity and mortality. In animal ARF models, effective treatments must be administered before or shortly after the insult, limiting their clinical potential. We used microarrays to identify early biomarkers that distinguish ischemic from nephrotoxic ARF or biomarkers that detect both injury types. We compared rat kidney transcriptomes at 2 and 8 h after ischemia/reperfusion and after mercuric chloride. Quality control and statistical analyses were necessary to normalize microarrays from different lots, eliminate outliers, and exclude unaltered genes. Principal component analysis revealed distinct ischemic and nephrotoxic trajectories and clear array groupings. Therefore, we used supervised analysis, t-tests, and fold changes to compile gene lists for each group, exclusive or nonexclusive, alone or in combination. There was little network connectivity, even in the largest group. Some microarray-identified genes were validated by TaqMan assay, ruling out artifacts. Western blotting confirmed that heme oxygenase-1 (HO-1) and activating transcription factor-3 (ATF3) proteins were upregulated; however, unexpectedly, their localization changed within the kidney. HO-1 staining shifted from cortical (early) to outer stripe of the outer medulla (late), primarily in detaching cells, after mercuric chloride but not ischemia/reperfusion. ATF3 staining was similar, but with additional early transient expression in the outer stripe after ischemia/reperfusion. We conclude that microarray-identified genes must be evaluated not only for protein levels but also for anatomical distribution among different zones, nephron segments, or cell types. Although protein detection reagents are limited, microarray data lay a rich foundation to explore biomarkers, therapeutics, and the pathophysiology of ARF.

Original languageEnglish
Pages (from-to)375-386
Number of pages12
JournalPhysiological Genomics
Volume25
Issue number3
DOIs
Publication statusPublished - 2006 May 16
Externally publishedYes

Fingerprint

Acute Kidney Injury
Activating Transcription Factor 3
Reperfusion
Mercuric Chloride
Heme Oxygenase-1
Ischemia
Biomarkers
Genes
Staining and Labeling
Kidney
Proteins
Nephrons
Principal Component Analysis
Transcriptome
Quality Control
Artifacts
Western Blotting
Morbidity
Mortality
Wounds and Injuries

Keywords

  • Immunohistochemistry
  • Microarray
  • Principal component analysis
  • Taqman
  • Western blots

ASJC Scopus subject areas

  • Physiology
  • Genetics

Cite this

Ischemic and nephrotoxic acute renal failure are distinguished by their broad transcriptomic responses. / Yuen, Peter S.T.; Jo, Sang Kyung; Holly, Mikaela K.; Hu, Xuzhen; Star, Robert A.

In: Physiological Genomics, Vol. 25, No. 3, 16.05.2006, p. 375-386.

Research output: Contribution to journalArticle

Yuen, Peter S.T. ; Jo, Sang Kyung ; Holly, Mikaela K. ; Hu, Xuzhen ; Star, Robert A. / Ischemic and nephrotoxic acute renal failure are distinguished by their broad transcriptomic responses. In: Physiological Genomics. 2006 ; Vol. 25, No. 3. pp. 375-386.
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