Acta Physiologica最新文献

{"title":"Beyond Being a Biomarker: Lipocalin-2/NGAL as a Facilitator for Protective Drug Action in Hypoxic Kidney Injury","authors":"Boye L. Jensen","doi":"10.1111/apha.70110","DOIUrl":"10.1111/apha.70110","url":null,"abstract":"<p>In the present issue of <i>Acta Physiologica</i> [<span>1</span>], an international consortium of investigators reports that the iron-transporter glycoprotein lipocalin-2 (LCN2), originally identified in neutrophils and named <i>neutrophil gelatinase-associated lipocalin</i>, abbreviated NGAL or 24p3, may protect the kidneys from ischemia–reperfusion injury. The findings suggest that LCN2 protects the kidneys by restoring the sensitivity of soluble guanylate cyclase (sGC) to drug activators in afferent glomerular arterioles through a receptor-mediated mechanism. LCN2 is produced and released by several tissues including adipose tissue, liver, kidneys, and neutrophils. It is categorized as an acute-phase protein that is upregulated during inflammatory states. LCN2 is widely used in clinical and experimental settings as an early biomarker in acute kidney injury and for the staging of chronic kidney disease.</p><p>The study by Zhao et al. [<span>1</span>] is an elegant follow-up study on a series of independent observations dating 10–20 years back, which include a study by authors from 2016 [<span>2</span>]. A consistent kidney-protective effect of exogenous LCN2 was found in preclinical kidney ischemia-injury models, including a kidney transplantation model. The study in <i>Acta</i> shows ex vivo with murine, isolated kidney microvessels, that LCN2 mitigates excessive microvascular resistance through restoring vascular smooth sGC sensitivity towards activator drugs. The sensitivity is typically lost by more severe prolonged hypoxia. Soluble GCs can be oxidized to the heme-free form, apo-sGC, and the authors confirm that apo-sGC cannot be activated by the endogenous agonist nitric oxide (NO). The class of sGC activator drugs is unique and different from sGC stimulators since they can overcome this state and activate apo-sGC independently of NO to increase target cell cyclic guanosine monophosphate (cGMP) production even under detrimental oxidative stress. Zhao et al. [<span>1</span>] show that LCN2 restores sensitivity of the kidney afferent arterioles towards sGC activators dependent on iron. The effect is found in arterioles subjected to hypoxia ex vivo after isolation and in arterioles subjected to hypoxia “in situ” in transplanted kidneys before microdissection and testing. The conclusion is that by delivering ferric iron bound to LCN2 (holo-LCN2) to arterioles, this oxidizes sGC, which restores sensitivity to activator drugs. The study corroborates that LCN2 may be a direct, extracellular, signaling molecule that indirectly protects vascular smooth muscle suffering from prolonged ischemic insults in the kidneys (Figure 1).</p><p>What is the mechanism? LCN2 binds hydrophobic microbial siderophores, which are small molecules that bacteria produce to sequester iron from their environment. The acute phase reactant LCN2 is thereby bacteriostatic since iron is a vital nutrient for many microbes. Deletion of LCN2 increases susceptibility to <i>Esch","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 10","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70110","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145123858","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}