BackgroundProlyl-4-hydroxylase domain-containing proteins 1–3 (PHD1 to PHD3) regulate the activity of the hypoxia-inducible factors (HIFs) HIF-1 and HIF-2, transcription factors that are key regulators of hypoxic vascular responses. We previously reported that deficiency of endothelial HIF-2 exacerbated renal ischemia-reperfusion injury, whereas inactivation of endothelial PHD2, the main oxygen sensor, provided renoprotection. Nevertheless, the molecular mechanisms by which endothelial PHD2 dictates AKI outcomes remain undefined.MethodsTo investigate the function of the endothelial PHD2/HIF axis in ischemic AKI, we examined the effects of endothelial-specific ablation of PHD2 in a mouse model of renal ischemia-reperfusion injury. We also interrogated the contribution of each HIF isoform by concurrent endothelial deletion of both PHD2 and HIF-1 or both PHD2 and HIF-2.ResultsEndothelial deletion of Phd2 preserved kidney function and limited transition to CKD. Mechanistically, we found that endothelial Phd2 ablation protected against renal ischemia-reperfusion injury by suppressing the expression of proinflammatory genes and recruitment of inflammatory cells in a manner that was dependent on HIF-1 but not HIF-2. Persistence of renoprotective responses after acute inducible endothelial-specific loss of Phd2 in adult mice ruled out a requirement for PHD2 signaling in hematopoietic cells. Although Phd2 inhibition was not sufficient to induce detectable HIF activity in the kidney endothelium, in vitro experiments implicated a humoral factor in the anti-inflammatory effects generated by endothelial PHD2/HIF-1 signaling.ConclusionsOur findings suggest that activation of endothelial HIF-1 signaling through PHD2 inhibition may offer a novel therapeutic approach against ischemic AKI.
Highlights d Hypoxia and PHD inhibition increase serum kynurenine d Ido1 deficiency blunts the increase in serum kynurenine by hypoxia and PHD inhibition d The IDO1-kynurenine axis is required in renoprotection by hypoxic preconditioning d Hypoxia and PHD inhibition activate the kynurenine pathway in the post-ischemic kidney
We report a case of severe systemic loxoscelism in a previously healthy young man. This was associated with a Coombs-positive hemolytic anemia, striking leukomid reaction, renal failure, respiratory failure and cardiovascular collapse. This is the first documented case of a renal biopsy in a patient with renal failure after envenomation by the brown recluse spider. Associated systemic toxicity usually resolves but requires prompt recognition and supportive care in an intensive care setting. We also discuss the potential mechanism by which the venom of this small spider can lead to multiorgan failure and possibly death.
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