The protective effect of prolyl-hydroxylase inhibition against renal ischaemia requires application prior to ischaemia but is superior to EPO treatment

Wang, Zhendi; Schley, Gunnar; Türkoglu, Gazi; Burzlaff, Nicolai; Amann, Kerstin; Willam, Carsten; Eckardt, Kai‐Uwe; Bernhardt, Wanja M.

doi:10.1093/ndt/gfr379

Cited by 77 publications

(76 citation statements)

References 41 publications

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“…In contrast to preconditioning with PHI, no clinical benefit was detected when PHI was administered following IRI, which may be explained by suboptimal induction of certain HIF target genes. While tissue acidosis and reactive oxygen species may have blunted transcriptional HIF responses in our model (11,34), absence of renoprotection was also reported in a recent study, where PHI was administered at the onset of reperfusion (33). In contrast, in a model of cerebral ischemia, PHD inhibitor dimethyloxaloylglycine increased HIF-regulated gene transcription and reduced injury when administered 30 or 60 min post-IRI (23).…”

Section: Discussionsupporting

confidence: 75%

Preischemic targeting of HIF prolyl hydroxylation inhibits fibrosis associated with acute kidney injury

Kapitsinou

Jaffe

Michael

et al. 2012

American Journal of Physiology-Renal Physiology

112

105

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-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...

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Section: Discussionsupporting

confidence: 75%

Preischemic targeting of HIF prolyl hydroxylation inhibits fibrosis associated with acute kidney injury

Kapitsinou

Jaffe

Michael

et al. 2012

American Journal of Physiology-Renal Physiology

112

105

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“…4-µm-thick sections were cut in a Leica microtome and stained with hematoxylin and eosin [23]. Stained sections of left kidneys were analyzed in a blinded manner by a pathologist as described [24,29]. The results were semiquantified using a scoring of 0–4: 0 = no abnormality; 1 = changes affecting up to 25% of the specimen; 2 = changes affecting up to 50% of the specimen; 3 = changes affecting up to 75% of the specimen; 4 = changes affecting >75% of the specimen.…”

Section: Methodsmentioning

confidence: 99%

Treatment with a Novel Hypoxia-Inducible Factor Hydroxylase Inhibitor (TRC160334) Ameliorates Ischemic Acute Kidney Injury

et al. 2012

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Background: Hypoxia-inducible factor (HIF) transcriptional system plays a central role in cellular adaptation to low oxygen levels. Preconditional activation of HIF and/or expression of its individual target gene products leading to cytoprotection have been well established in hypoxic/ischemic renal injury. Increasing evidence indicate HIF activation is involved in hypoxic/ischemic postconditioning of heart, brain and kidney. Very few studies evaluated the potential benefits of postischemia HIF activation in renal injury employing a pharmacological agent. We hypothesized that postischemia augmentation of HIF activation with a pharmacological agent would protect renal ischemia/reperfusion injury. For this, TRC160334, a novel HIF hydroxylase inhibitor, was used. Methods: TRC160334, a novel HIF hydroxylase inhibitor, was synthesized. Ability of TRC160334 for stabilization of HIF-α and consequent HIF activation was evaluated in Hep3B cells. Efficacy of TRC160334 was evaluated in a rat model of ischemia/reperfusion-induced AKI. Two different treatment protocols were employed, one involved treatment with TRC160334 before onset of ischemia, the other involved treatment after the reperfusion of kidneys. Results: TRC160334 treatment results in stabilization of HIF-α leading to HIF activation in Hep3B cells. Significant reduction in renal injury was observed by both treatment protocols and remarkable reduction in serum creatinine (23 and 71% at 24 and 48 h, respectively, p < 0.01) was observed with TRC160334 treatment applied after reperfusion. Urine output was significantly improved up to 24 h by both treatment protocols. Conclusion: The data presented here provide pharmacologic evidence for postischemia augmentation of HIF activation by TRC160334 as a promising and clinically feasible strategy for the treatment of renal ischemia/reperfusion injury.

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“…We then tested if HIF stabilization affects P2Y2R expression in plMDCK cells. Cells were incubated with the PHD inhibitor 2-(1-chloro-4-hydroxyisoquinoline-3-carboxamido) acetate (ICA) which is more feasible for long-term experiments than DMOG due to less toxicity [5,22]. ICA led to an increase of P2Y2R signal in the apical membrane of plMDCK cells in control-transfected cells whereas ICA had no or only little effect in P2Y2R-deficient cells (Fig.…”

Section: P2y2r Is Expressed In Cyst-lining Epithelial Cellsmentioning

confidence: 99%

P2Y2R is a direct target of HIF-1α and mediates secretion-dependent cyst growth of renal cyst-forming epithelial cells

Kraus

Grampp

Goppelt‐Struebe

et al. 2016

Purinergic Signalling

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Polycystic kidney diseases are characterized by numerous renal cysts that continuously enlarge resulting in compression of intact nephrons and tissue hypoxia. Recently, we have shown that hypoxia-inducible factor (HIF)-1α promotes secretion-dependent cyst expansion, presumably by transcriptional regulation of proteins that are involved in calciumactivated chloride secretion. Here, we report that HIF-1α directly activates expression of the purinergic receptor P2Y2R in human primary renal tubular cells. In addition, we found that P2Y2R is highly expressed in cyst-lining cells of human ADPKD kidneys as well as PKD1 orthologous mouse kidneys. Knockdown of P2Y2R in renal collecting duct cells inhibited calcium-dependent chloride secretion in Ussing chamber analyses. In line with these findings, knockdown of P2Y2R retarded cyst expansion in vitro and prevented ATPand HIF-1α-dependent cyst growth. In conclusion, P2Y2R mediates ATP-dependent cyst growth and is transcriptionally regulated by HIF-1α. These findings provide further mechanistic evidence on how hypoxia promotes cyst growth.

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The protective effect of prolyl-hydroxylase inhibition against renal ischaemia requires application prior to ischaemia but is superior to EPO treatment

Cited by 77 publications

References 41 publications

Preischemic targeting of HIF prolyl hydroxylation inhibits fibrosis associated with acute kidney injury

Preischemic targeting of HIF prolyl hydroxylation inhibits fibrosis associated with acute kidney injury

Treatment with a Novel Hypoxia-Inducible Factor Hydroxylase Inhibitor (TRC160334) Ameliorates Ischemic Acute Kidney Injury

P2Y2R is a direct target of HIF-1α and mediates secretion-dependent cyst growth of renal cyst-forming epithelial cells

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