Liang Zhao, Minze Xu, Anna Maria Pfefferkorn, Cem Erdogan, Hubert Schwelberger, Pinchao Wang, Pratik Hemant Khedkar, Marc Eigen, Falk-Bach Lichtenberger, Rusan Catar, En Yin Lai, Felix Aigner, Pontus B. Persson, Igor Maximilian Sauer, Andreas Patzak, Muhammad Imtiaz Ashraf
{"title":"脂钙素-2恢复小鼠肾移植或体外缺氧/再氧化后传入小动脉的可溶性关酰环化酶依赖性扩张","authors":"Liang Zhao, Minze Xu, Anna Maria Pfefferkorn, Cem Erdogan, Hubert Schwelberger, Pinchao Wang, Pratik Hemant Khedkar, Marc Eigen, Falk-Bach Lichtenberger, Rusan Catar, En Yin Lai, Felix Aigner, Pontus B. Persson, Igor Maximilian Sauer, Andreas Patzak, Muhammad Imtiaz Ashraf","doi":"10.1111/apha.70077","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Aim</h3>\n \n <p>Dilatory microvascular function is impaired in ischemia/reperfusion injury in the kidney. Nitric oxide independent activators of soluble guanylyl cyclase (sGC) provide renal protection by dilating microvessels and preserving perfusion, but their efficacy declines after severe hypoxia. This study explores whether lipocalin-2 (Lcn2), a key iron-transporting protein, can restore the sGC-mediated dilation in mouse afferent arterioles (AAs) after hypoxia/reoxygenation (<i>H</i>/<i>R</i>) and kidney transplantation.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>Dilation of isolated, angiotensin II (Ang II) pre-constricted, AAs was induced by application of sGC activator cinaciguat after pre-constriction with Ang II following <i>H</i>/<i>R</i> (<i>H</i>: 30 min, <i>R</i>: 10 min ± holo-rLcn2, apo-rLcn2, deferoxamine) and syngeneic kidney transplantation (cold ischemia: 30 min or 5.5 h, reperfusion: 20 h ± holo-rLcn2) in C57BL/6 mice. To corroborate the dilatory function at the organ level, vascular relaxation was assessed using an isolated mouse kidney perfusion system.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>Dilation of AAs was impaired following <i>H</i>/<i>R</i>. Pretreatment with holo-rLcn2 (iron-bound) preserved dilation, whereas apo-rLcn2 (iron-free) had no effect. The reversal of holo-rLcn2's effect by deferoxamine confirmed the role of iron. AAs from kidney transplants showed reduced dilation compared to sham-operated controls, with greater impairment following prolonged ischemia. Treatment with holo-rLcn2 significantly improved dilatory function after extended cold ischemia (5.5 h), restoring it to levels seen with shorter ischemia (30 min). Ex vivo perfusion of the isolated mouse kidney with holo-rLcn2 enhanced cinaciguat-induced vascular relaxation, confirming its beneficial effect at the organ level.</p>\n </section>\n \n <section>\n \n <h3> Conclusion</h3>\n \n <p>This study identifies a novel role for holo-rLcn2 in preserving renal vascular function post-<i>H</i>/<i>R</i> and kidney transplantation, apparently by upholding iron levels in vascular cells.</p>\n </section>\n </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 8","pages":""},"PeriodicalIF":5.6000,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70077","citationCount":"0","resultStr":"{\"title\":\"Lipocalin-2 Restores Soluble Guanylyl Cyclase-Dependent Dilation of the Afferent Arteriole After Renal Transplantation or Ex Vivo Hypoxia/Reoxygenation in Mice\",\"authors\":\"Liang Zhao, Minze Xu, Anna Maria Pfefferkorn, Cem Erdogan, Hubert Schwelberger, Pinchao Wang, Pratik Hemant Khedkar, Marc Eigen, Falk-Bach Lichtenberger, Rusan Catar, En Yin Lai, Felix Aigner, Pontus B. Persson, Igor Maximilian Sauer, Andreas Patzak, Muhammad Imtiaz Ashraf\",\"doi\":\"10.1111/apha.70077\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <h3> Aim</h3>\\n \\n <p>Dilatory microvascular function is impaired in ischemia/reperfusion injury in the kidney. Nitric oxide independent activators of soluble guanylyl cyclase (sGC) provide renal protection by dilating microvessels and preserving perfusion, but their efficacy declines after severe hypoxia. This study explores whether lipocalin-2 (Lcn2), a key iron-transporting protein, can restore the sGC-mediated dilation in mouse afferent arterioles (AAs) after hypoxia/reoxygenation (<i>H</i>/<i>R</i>) and kidney transplantation.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Methods</h3>\\n \\n <p>Dilation of isolated, angiotensin II (Ang II) pre-constricted, AAs was induced by application of sGC activator cinaciguat after pre-constriction with Ang II following <i>H</i>/<i>R</i> (<i>H</i>: 30 min, <i>R</i>: 10 min ± holo-rLcn2, apo-rLcn2, deferoxamine) and syngeneic kidney transplantation (cold ischemia: 30 min or 5.5 h, reperfusion: 20 h ± holo-rLcn2) in C57BL/6 mice. To corroborate the dilatory function at the organ level, vascular relaxation was assessed using an isolated mouse kidney perfusion system.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Results</h3>\\n \\n <p>Dilation of AAs was impaired following <i>H</i>/<i>R</i>. Pretreatment with holo-rLcn2 (iron-bound) preserved dilation, whereas apo-rLcn2 (iron-free) had no effect. The reversal of holo-rLcn2's effect by deferoxamine confirmed the role of iron. AAs from kidney transplants showed reduced dilation compared to sham-operated controls, with greater impairment following prolonged ischemia. Treatment with holo-rLcn2 significantly improved dilatory function after extended cold ischemia (5.5 h), restoring it to levels seen with shorter ischemia (30 min). Ex vivo perfusion of the isolated mouse kidney with holo-rLcn2 enhanced cinaciguat-induced vascular relaxation, confirming its beneficial effect at the organ level.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Conclusion</h3>\\n \\n <p>This study identifies a novel role for holo-rLcn2 in preserving renal vascular function post-<i>H</i>/<i>R</i> and kidney transplantation, apparently by upholding iron levels in vascular cells.</p>\\n </section>\\n </div>\",\"PeriodicalId\":107,\"journal\":{\"name\":\"Acta Physiologica\",\"volume\":\"241 8\",\"pages\":\"\"},\"PeriodicalIF\":5.6000,\"publicationDate\":\"2025-07-04\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70077\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Acta Physiologica\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1111/apha.70077\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"PHYSIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Acta Physiologica","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/apha.70077","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHYSIOLOGY","Score":null,"Total":0}
Lipocalin-2 Restores Soluble Guanylyl Cyclase-Dependent Dilation of the Afferent Arteriole After Renal Transplantation or Ex Vivo Hypoxia/Reoxygenation in Mice
Aim
Dilatory microvascular function is impaired in ischemia/reperfusion injury in the kidney. Nitric oxide independent activators of soluble guanylyl cyclase (sGC) provide renal protection by dilating microvessels and preserving perfusion, but their efficacy declines after severe hypoxia. This study explores whether lipocalin-2 (Lcn2), a key iron-transporting protein, can restore the sGC-mediated dilation in mouse afferent arterioles (AAs) after hypoxia/reoxygenation (H/R) and kidney transplantation.
Methods
Dilation of isolated, angiotensin II (Ang II) pre-constricted, AAs was induced by application of sGC activator cinaciguat after pre-constriction with Ang II following H/R (H: 30 min, R: 10 min ± holo-rLcn2, apo-rLcn2, deferoxamine) and syngeneic kidney transplantation (cold ischemia: 30 min or 5.5 h, reperfusion: 20 h ± holo-rLcn2) in C57BL/6 mice. To corroborate the dilatory function at the organ level, vascular relaxation was assessed using an isolated mouse kidney perfusion system.
Results
Dilation of AAs was impaired following H/R. Pretreatment with holo-rLcn2 (iron-bound) preserved dilation, whereas apo-rLcn2 (iron-free) had no effect. The reversal of holo-rLcn2's effect by deferoxamine confirmed the role of iron. AAs from kidney transplants showed reduced dilation compared to sham-operated controls, with greater impairment following prolonged ischemia. Treatment with holo-rLcn2 significantly improved dilatory function after extended cold ischemia (5.5 h), restoring it to levels seen with shorter ischemia (30 min). Ex vivo perfusion of the isolated mouse kidney with holo-rLcn2 enhanced cinaciguat-induced vascular relaxation, confirming its beneficial effect at the organ level.
Conclusion
This study identifies a novel role for holo-rLcn2 in preserving renal vascular function post-H/R and kidney transplantation, apparently by upholding iron levels in vascular cells.
期刊介绍：
Acta Physiologica is an important forum for the publication of high quality original research in physiology and related areas by authors from all over the world. Acta Physiologica is a leading journal in human/translational physiology while promoting all aspects of the science of physiology. The journal publishes full length original articles on important new observations as well as reviews and commentaries.
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