Inhibition of Endothelial PHD2 Suppresses Post-Ischemic Kidney Inflammation through Hypoxia-Inducible Factor-1.

Autor:	Rajendran G; Department of Medicine, Anatomy and Cell Biology and.; The Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas; and., Schonfeld MP; Department of Medicine, Anatomy and Cell Biology and.; The Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas; and., Tiwari R; Department of Medicine, Anatomy and Cell Biology and.; The Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas; and., Huang S; Department of Medicine, Anatomy and Cell Biology and.; The Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas; and., Torosyan R; Department of Medicine, Anatomy and Cell Biology and.; The Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas; and., Fields T; The Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas; and., Park J; Renal Electrolyte and Hypertension Division, Department of Medicine and Genetics, University of Pennsylvania, Philadelphia, Pennsylvania., Susztak K; Renal Electrolyte and Hypertension Division, Department of Medicine and Genetics, University of Pennsylvania, Philadelphia, Pennsylvania., Kapitsinou PP; Department of Medicine, Anatomy and Cell Biology and pinelopi.kapitsinou@northwestern.edu.; The Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas; and.
Jazyk:	angličtina
Zdroj:	Journal of the American Society of Nephrology : JASN [J Am Soc Nephrol] 2020 Mar; Vol. 31 (3), pp. 501-516. Date of Electronic Publication: 2020 Jan 29.
DOI:	10.1681/ASN.2019050523
Abstrakt:	Background: Prolyl-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. Methods: To 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. Results: Endothelial 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. Conclusions: Our findings suggest that activation of endothelial HIF-1 signaling through PHD2 inhibition may offer a novel therapeutic approach against ischemic AKI. (Copyright © 2020 by the American Society of Nephrology.)
Databáze:	MEDLINE
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