ABSTRACT
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.
Subject(s)
Acute Kidney Injury/prevention & control , Hypoxia-Inducible Factor 1/metabolism , Kidney/pathology , Procollagen-Proline Dioxygenase/antagonists & inhibitors , Transcription Factors/metabolism , Acute Kidney Injury/chemically induced , Acute Kidney Injury/metabolism , Animals , Disease Models, Animal , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Fibrosis , Hydroxylation/drug effects , Male , Mice , Mice, Inbred C57BL , Procollagen-Proline Dioxygenase/metabolism , Xylazine/adverse effectsABSTRACT
Hypertension is a well established risk factor for cardiovascular diseases such as stroke and is the leading cause of chronic kidney failure. Although a number of pharmacologic agents are available for the treatment of hypertension including agents that affect the renin-angiotensin-aldosterone system (RAAS), unmet needs in the treatment of hypertension suggest that identification of novel pharmacological targets would be an important healthcare goal. One potential target is prostaglandin E(2) (PGE(2)), a potent lipid mediator with a diverse and sometimes opposing range of biological effects. PGE(2) signals through four subtypes of G-protein coupled receptors designated EP1 through EP4. PGE(2) functions primarily as a vasodepressor; under certain conditions PGE(2) administration mediates vasopressor activity. This review focuses on the current understanding of the roles of PGE(2) receptors in vascular reactivity, hypertension and end-organ damage.
