-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.hypoxia-inducible factor; HIF prolyl-4-hydroxylases ISCHEMIA-REPERFUSION INJURY (IRI) in the kidney is a major cause of acute kidney injury (AKI). Despite advances in understanding the pathophysiology of AKI and important improvements in clinical care, the overall prognosis of patients with AKI remains poor and is associated with a mortality rate of 40 -80% in the intensive care setting (31). Similarly, preventive strategies have been unsuccessful as the incidence of AKI is increasing and will nearly double over the next decade as the population ages (1). In addition to challenges of acute clinical management, AKI is increasingly recognized as an important contributor to end-stage renal disease (ESRD) (1,8,16,20); ϳ6% of patients with AKI progress to ESRD within 2 yr of diagnosis (29). Similarly, animal studies examining long-term outcomes of AKI have detected irreversible functional and structural changes, including tubulointerstitial fibrosis and capillary rarefaction. These facts highlight the urgent need for novel therapeutic approaches that aim at preventing and/or reversing the pathophysiologic sequelae of AKI.Hypoxic preconditioning, by which short exposure to hypoxia induces resistance to subsequent ischemic injury, has received much attention as a potential novel therapeutic strategy in the prevention of AKI (12). Key mediators of cellular adaptation to oxygen deprivation are hypoxia-inducible factor (HIF)-1 and -2, heterodimeric basic helix-loop-helix transcription factors, which regulate cellular energy metabolism, angiogenesis, erythropoiesis, apoptosis, and cell proliferation. The activity of HIF is controlled by oxygen-, iron-, and ascorbatedependent dioxygenases, also known as prolyl-4-hydroxylase domain-containing proteins 1-3 (PHD1-3), which use 2-oxoglutarate as substrate for the hydroxylation of specific proline residues in HIF-␣. This permits binding to the pVHL-E3 ubiquitin ligase complex, which results in proteasomal degradation of HIF...

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 E2 (PGE2), a potent lipid mediator with a diverse and sometimes opposing range of biological effects. PGE2 signals through four subtypes of G-protein coupled receptors designated EP1 through EP4. PGE2 functions primarily as a vasodepressor; under certain conditions PGE2 administration mediates vasopressor activity. This review focuses on the current understanding of the roles of PGE2 receptors in vascular reactivity, hypertension and end-organ damage.

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