Open AccessPreischemic targeting of HIF prolyl hydroxylation inhibits fibrosis associated with acute kidney injury
Author(s) -
Pinelopi P. Kapitsinou,
Jonathan T. Jaffe,
Mark Michael,
Christina E. Swan,
Kevin J. Duffy,
Connie L. EricksonMiller,
Volker H. Haase
Publication year - 2012
Publication title -
american journal of physiology. renal physiology./american journal of physiology. renal physiology
Language(s) - English
Resource type - Journals
eISSN - 1931-857X
pISSN - 1522-1466
DOI - 10.1152/ajprenal.00667.2011
Subject(s) - acute kidney injury , fibrosis , medicine , hypoxia (environmental) , kidney disease , inflammation , hydroxylation , ischemia , kidney , pharmacology , hypoxia inducible factors , oxygen , chemistry , biochemistry , enzyme , organic chemistry , gene
Acute kidney injury (AKI) due to ischemia is an important contributor to the progression of chronic kidney disease (CKD). Key mediators of cellular adaptation to hypoxia are oxygen-sensitive hypoxia-inducible factors (HIF), which are regulated by prolyl-4-hydroxylase domain (PHD)-containing dioxygenases. While activation of HIF protects from ischemic cell death, HIF has been shown to promote fibrosis in experimental models of CKD. The impact of HIF activation on AKI-induced fibrosis has not been defined. Here, we investigated the role of pharmacologic HIF activation in AKI-associated fibrosis and inflammation. We found that pharmacologic inhibition of HIF prolyl hydroxylation before AKI ameliorated fibrosis and prevented anemia, while inhibition of HIF prolyl hydroxylation in the early recovery phase of AKI did not affect short- or long-term clinical outcome. Therefore, preischemic targeting of the PHD/HIF pathway represents an effective therapeutic strategy for the prevention of CKD resulting from AKI, and it warrants further investigation in clinical trials.