Progressive endothelin-1 gene activation initiates chronic/end-stage renal disease following experimental ischemic/reperfusion injury.

Abstract

This study assessed whether endothelin-1 (ET-1) helps mediate postischemic acute kidney injury (AKI) progression to chronic kidney disease (CKD). The impact(s) of potent ETA or ETB receptor-specific antagonists (Atrasentan and BQ-788, respectively) on disease progression were assessed 24 h or 2 weeks following 30 min of unilateral ischemia in CD-1 mice. Unilateral ischemia caused progressive renal ET-1 protein/mRNA increases with concomitant ETA, but not ETB, mRNA elevations. Extensive histone remodeling consistent with gene activation and increased RNA polymerase II (Pol II) binding occurred at the ET-1 gene. Unilateral ischemia produced progressive renal injury as indicated by severe histologic injury and a 40% loss of renal mass. Pre- and post-ischemia or just postischemic treatment with Atrasentan conferred dramatic protective effects such as decreased tubule/microvascular injury, normalized tissue lactate, and total preservation of renal mass. Nuclear KI-67 staining was not increased by Atrasentan, implying that increased tubule proliferation was not involved. Conversely, ETB blockade had no protective effect. Thus, our findings provide the first evidence that ET-1 operating through ETA can have a critical role in ischemic AKI progression to CKD. Blockade of ETA provided dramatic protection, indicating the functional significance of these results.

• Authors: Richard A Zager, Ali C M Johnson, Dennis Andress, Kirsten Becker
• Journal: Kidney international (Kidney Int) Vol. 84 Issue 4 Pg. 703-12 (Oct 2013) ISSN: 1523-1755 [Electronic] United States
• PMID: 23698233 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Endothelin A Receptor Antagonists
• Endothelin B Receptor Antagonists
• Endothelin-1
• Oligopeptides
• Piperidines
• Pyrrolidines
• RNA, Messenger
• Receptor, Endothelin A
• Receptor, Endothelin B
• BQ 788
• Atrasentan

Topics

• Animals
• Atrasentan
• Disease Models, Animal
• Disease Progression
• Endothelin A Receptor Antagonists
• Endothelin B Receptor Antagonists
• Endothelin-1 (genetics, physiology)
• Kidney Failure, Chronic (etiology, physiopathology)
• Male
• Mice
• Mice, Inbred Strains
• Oligopeptides (pharmacology)
• Piperidines (pharmacology)
• Pyrrolidines (pharmacology)
• RNA, Messenger (genetics)
• Receptor, Endothelin A (drug effects, physiology)
• Receptor, Endothelin B (drug effects, physiology)
• Renal Insufficiency, Chronic (etiology, physiopathology)
• Reperfusion Injury (complications, physiopathology)