ArticleJournal of the American Society of Nephrology : JASN2009
Distinct functions of activated protein C differentially attenuate acute kidney injury.
Article in Journal of the American Society of Nephrology : JASN, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
21 citing papers in PubMed, 1 synthesis or guideline pooled it, 53 citations in OpenAlex.
- Prevention of acute kidney injury and protection of renal function in the intensive care unit. Expert opinion of the Working Group for Nephrology, ESICM.Intensive care medicine · 2010Guideline
- Recombinant human activated protein C attenuates cardiovascular and microcirculatory dysfunction in acute lung injury and septic shock.Critical care (London, England) · 2010Trial
- Protective Factors and the Pathogenesis of Complications in Diabetes.Endocrine reviews · 2024Review
- Identification of Endothelial Cell Protein C Receptor by Urinary Proteomics as Novel Prognostic Marker in Non-Recovery Kidney Injury.International journal of molecular sciences · 2024Article
- Role of coagulation in persistent renal ischemia following reperfusion in an animal model.American journal of physiology. Renal physiology · 2022Article
- Neuroprotective Effects of Activated Protein C Involve the PARP/AIF Pathway against Oxygen-Glucose Deprivation in SH-SY5Y Cells.Brain sciences · 2020Article
- Activated Protein C in Cutaneous Wound Healing: From Bench to Bedside.International journal of molecular sciences · 2019Review
- Diabetic Microvascular Disease: An Endocrine Society Scientific Statement.The Journal of clinical endocrinology and metabolism · 2017Review
- Targeting PAR1: Now What?Trends in pharmacological sciences · 2017Review
- Activated Protein C Ameliorates Renal Ischemia-Reperfusion Injury by Restricting Y-Box Binding Protein-1 Ubiquitination.Journal of the American Society of Nephrology : JASN · 2015Article
- A Friend in Need: Activated Protein C Stabilizes YB-1 during Renal Ischemia Reperfusion Injury.Journal of the American Society of Nephrology : JASN · 2015Article
- Abrogation of plasminogen activator inhibitor-1-vitronectin interaction ameliorates acute kidney injury in murine endotoxemia.PloS one · 2015Article
- Cytoprotective-selective activated protein C therapy for ischaemic stroke.Thrombosis and haemostasis · 2014Review
- Activated protein C ameliorates impaired renal microvascular oxygenation and sodium reabsorption in endotoxemic rats.Intensive care medicine experimental · 2013Article
- Bench-to-bedside review: Ventilation-induced renal injury through systemic mediator release--just theory or a causal relationship?Critical care (London, England) · 2011Review
- Pathogenesis of acute kidney injury: foundation for clinical practice.American journal of kidney diseases : the official journal of the National Kidney Foundation · 2011Review
- Pathophysiology of ischemic acute kidney injury.Nature reviews. Nephrology · 2011Review
- Thrombin down-regulates the TGF-beta-mediated synthesis of collagen and fibronectin by human proximal tubule epithelial cells through the EPCR-dependent activation of PAR-1.Journal of cellular physiology · 2010Article
- Activated protein C for H1N1 influenza? More work to do!Critical care (London, England) · 2010Article
- Activated protein C ameliorates coagulopathy but does not influence outcome in lethal H1N1 influenza: a controlled laboratory study.Critical care (London, England) · 2010Article
Corrections and comments
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Administration of activated protein C (APC) protects from renal dysfunction, but the underlying mechanism is unknown. APC exerts both antithrombotic and cytoprotective properties, the latter via modulation of protease-activated receptor-1 (PAR-1) signaling. We generated APC variants to study the relative importance of the two functions of APC in a model of LPS-induced renal microvascular dysfunction. Compared with wild-type APC, the K193E variant exhibited impaired anticoagulant activity but retained the ability to mediate PAR-1-dependent signaling. In contrast, the L8W variant retained anticoagulant activity but lost its ability to modulate PAR-1. By administering wild-type APC or these mutants in a rat model of LPS-induced injury, we found that the PAR-1 agonism, but not the anticoagulant function of APC, reversed LPS-induced systemic hypotension. In contrast, both functions of APC played a role in reversing LPS-induced decreases in renal blood flow and volume, although the effects on PAR-1-dependent signaling were more potent. Regarding potential mechanisms for these findings, APC-mediated PAR-1 agonism suppressed LPS-induced increases in the vasoactive peptide adrenomedullin and infiltration of iNOS-positive leukocytes into renal tissue. However, the anticoagulant function of APC was responsible for suppressing LPS-induced stimulation of the proinflammatory mediators ACE-1, IL-6, and IL-18, perhaps accounting for its ability to modulate renal hemodynamics. Both variants reduced active caspase-3 and abrogated LPS-induced renal dysfunction and pathology. We conclude that although PAR-1 agonism is solely responsible for APC-mediated improvement in systemic hemodynamics, both functions of APC play distinct roles in attenuating the response to injury in the kidney.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.