{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T14:01:59Z","timestamp":1756994519754,"version":"3.41.2"},"reference-count":28,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,3,31]],"date-time":"2022-03-31T00:00:00Z","timestamp":1648684800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81770671","82090021"],"award-info":[{"award-number":["81770671","82090021"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Complement dysregulation has been implicated in the pathogenesis of malignant nephrosclerosis with typical pathological manifestation as thrombotic microangiopathy (TMA) in recent studies. The aim of the present study was to evaluate the potential role of complement activation in arterionephrosclerosis, the major pathological change in benign hypertensive nephrosclerosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Patients with biopsy-proven arterionephrosclerosis from 2010 to 2018 in our center were retrospectively enrolled in the present study. The clinical data were retrieved from the medical chart record. The pathological changes of renal biopsy were semiquantitatively evaluated. The ratio of inner-\/outer-luminal diameter of the arterioles was calculated to evaluate the degree of arteriosclerosis. Immunohistochemical staining of CD34 and CD68 was adopted to evaluate peritubular capillary (PTC) density and macrophage infiltration, respectively. Complement components, including C3d, C4d, C1q, and C5b-9, were detected by immunohistochemical staining in paraffin-embedded sections. IgM and albumin were detected by immunofluorescence staining in frozen renal tissues.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Fifty-two patients were enrolled. The mean age was 45.0 \u00b1 12.7 years, with 39 (75%) males. The median duration of hypertension was 66 months (IQR: 24\u2013138 months). A total of 950 arterioles were evaluated, with a mean ratio of the inner\/outer luminal diameter of 0.43 \u00b1 0.05. The ratio of the inner-\/outer-luminal diameter correlated with eGFR (<jats:italic>r<\/jats:italic> = 0.341, <jats:italic>p<\/jats:italic> = 0.013), sclerotic\/ischemic glomerular lesions (<jats:italic>r<\/jats:italic> = \u20130.364, <jats:italic>p<\/jats:italic> = 0.008) and PTC density (<jats:italic>r<\/jats:italic> = 0.426, <jats:italic>p<\/jats:italic> = 0.002). Seventy-four percent (703\/950) of the evaluated arterioles had C3d deposition with various patterns and intensities. The percentage of C3d-positive arterioles ranged from 63.6 to 100.0% in each specimen. The ratio of the inner\/outer luminal diameter of arterioles correlated with the intensity of C3d deposition (<jats:italic>r<\/jats:italic> = \u20130.174, <jats:italic>p<\/jats:italic> = 0.001). Infiltration of macrophages was observed around C3d-positive arterioles. The percentage of C3d-positive arterioles was correlated with macrophage infiltration in each specimen (<jats:italic>r<\/jats:italic> = 0.330, <jats:italic>p<\/jats:italic> = 0.018). Occasional C4d-positive staining on arterioles was observed with no deposition of C1q or C5b-9 in arterionephrosclerosis specimens.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our findings provide evidence for potential complement activation in the pathogenesis of vascular lesions in arterionephrosclerosis.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fmed.2022.836155","type":"journal-article","created":{"date-parts":[[2022,3,31]],"date-time":"2022-03-31T09:47:34Z","timestamp":1648720054000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Potential Involvement of Complement Activation in Kidney Vascular Lesions of Arterionephrosclerosis"],"prefix":"10.3389","volume":"9","author":[{"given":"Xuejing","family":"Chen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaojuan","family":"Yu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suxia","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Minghui","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,3,31]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e21","DOI":"10.1053\/j.ajkd.2016.02.035","article-title":"AJKD atlas of renal pathology: arterionephrosclerosis.","volume":"674","author":"Lusco","year":"2016","journal-title":"Am J Kidney Dis."},{"key":"B2","doi-asserted-by":"publisher","first-page":"557","DOI":"10.2215\/CJN.11470918","article-title":"Etiology and outcomes of thrombotic microangiopathies.","volume":"144","author":"Bayer","year":"2019","journal-title":"Clin J Am Soc Nephrol."},{"key":"B3","doi-asserted-by":"crossref","first-page":"300","DOI":"10.2215\/CJN.00620117","article-title":"Thrombotic microangiopathy and the kidney.","volume":"132","author":"Brocklebank","year":"2018","journal-title":"Clin J Am Soc Nephrol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.ekir.2020.10.009","article-title":"Complement in secondary thrombotic microangiopathy.","volume":"61","author":"Palma","year":"2021","journal-title":"Kidney Int Rep."},{"key":"B5","doi-asserted-by":"publisher","first-page":"2239","DOI":"10.1681\/ASN.2014050429","article-title":"Complement factor C4d is a common denominator in thrombotic microangiopathy.","volume":"269","author":"Chua","year":"2015","journal-title":"J Am Soc Nephrol."},{"key":"B6","doi-asserted-by":"crossref","first-page":"1222","DOI":"10.1093\/ndt\/gfaa280","article-title":"Association between thrombotic microangiopathy and activated alternative complement pathway in malignant nephrosclerosis.","volume":"36","author":"Zhang","year":"2020","journal-title":"Nephrol Dial Transplant."},{"key":"B7","doi-asserted-by":"publisher","first-page":"995","DOI":"10.1016\/j.kint.2019.05.014","article-title":"Severe and malignant hypertension are common in primary atypical hemolytic uremic syndrome.","volume":"964","author":"Cavero","year":"2019","journal-title":"Kidney Int."},{"key":"B8","doi-asserted-by":"publisher","first-page":"276","DOI":"10.1038\/sj.jhh.1002129","article-title":"Plasma levels of complement C3 is associated with development of hypertension: a longitudinal cohort study.","volume":"214","author":"Engstrom","year":"2007","journal-title":"J Hum Hyperten."},{"key":"B9","doi-asserted-by":"publisher","first-page":"218","DOI":"10.1111\/imr.12462","article-title":"Complement in removal of the dead - balancing inflammation.","volume":"2741","author":"Martin","year":"2016","journal-title":"Immunol Rev."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1636","DOI":"10.2215\/CJN.06230614","article-title":"Molecules great and small: the complement system.","volume":"109","author":"Mathern","year":"2015","journal-title":"Clin J Am Soc Nephrol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1111\/imr.12500","article-title":"Complement component C3 - The \u201cSwiss Army Knife\u201d of innate immunity and host defense.","volume":"2741","author":"Ricklin","year":"2016","journal-title":"Immunol Rev."},{"key":"B12","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1385\/IR:36:1:197","article-title":"Complement-mediated activation of the adaptive immune responses: role of C3d in linking the innate and adaptive immunity.","volume":"36","author":"Toapanta","year":"2006","journal-title":"Immunol Res."},{"key":"B13","doi-asserted-by":"publisher","first-page":"2294","DOI":"10.1093\/eurheartj\/ehi339","article-title":"Complement component C5a predicts future cardiovascular events in patients with advanced atherosclerosis.","volume":"2621","author":"Speidl","year":"2005","journal-title":"Eur Heart J."},{"key":"B14","doi-asserted-by":"publisher","first-page":"H349","DOI":"10.1152\/ajpheart.00759.2016","article-title":"A pathogenic role of complement in arterial hypertension and hypertensive end organ damage.","volume":"3123","author":"Wenzel","year":"2017","journal-title":"Am J Physiol Heart Circ Physiol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"2849","DOI":"10.1111\/bph.15171","article-title":"The role of complement in arterial hypertension and hypertensive end organ damage.","volume":"17814","author":"Wenzel","year":"2021","journal-title":"Br J Pharmacol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1182","DOI":"10.1093\/ndt\/gfy121","article-title":"Clinicopathological predictors for progression of chronic kidney disease in nephrosclerosis: a biopsy-based cohort study.","volume":"347","author":"Yamanouchi","year":"2019","journal-title":"Nephrol Dial Transplant."},{"key":"B17","doi-asserted-by":"publisher","first-page":"266","DOI":"10.1097\/MNH.0b013e3282f88a1f","article-title":"Hypertensive nephrosclerosis.","volume":"173","author":"Hill","year":"2008","journal-title":"Curr Opin Nephrol Hypertens."},{"key":"B18","doi-asserted-by":"publisher","first-page":"594","DOI":"10.2353\/ajpath.2010.090268","article-title":"Human nephrosclerosis triggers a hypoxia-related glomerulopathy.","volume":"1762","author":"Neusser","year":"2010","journal-title":"Am J Pathol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1833","DOI":"10.1093\/ndt\/gfu366","article-title":"Nephrosclerosis: update on a centenarian.","volume":"3011","author":"Meyrier","year":"2015","journal-title":"Nephrol Dial Transplant."},{"key":"B20","first-page":"158","article-title":"Inflammation, immunity, and hypertension.","volume":"492","author":"Agita","year":"2017","journal-title":"Acta Med Indones."},{"key":"B21","doi-asserted-by":"publisher","first-page":"677","DOI":"10.1111\/j.1751-7176.2008.00002.x","article-title":"Resistant arterial hypertension is associated with higher blood levels of complement C3 and C-reactive protein.","volume":"109","author":"Magen","year":"2008","journal-title":"J Clin Hypertens (Greenwich)."},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0042010","article-title":"Associations of CFH polymorphisms and CFHR1-CFHR3 deletion with blood pressure and hypertension in Chinese population.","volume":"77","author":"Gan","year":"2012","journal-title":"PLoS One."},{"key":"B23","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1016\/j.anndiagpath.2014.01.001","article-title":"C3d deposition in the media of renal arterioles is a useful marker for arteriolosclerosis in IgA nephropathy.","volume":"182","author":"Zhang","year":"2014","journal-title":"Ann Diagn Pathol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"2234","DOI":"10.1681\/ASN.2018020184","article-title":"C5b9 Formation on endothelial cells reflects complement defects among patients with renal thrombotic microangiopathy and severe hypertension.","volume":"298","author":"Timmermans","year":"2018","journal-title":"J Am Soc Nephrol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1420","DOI":"10.1016\/j.kint.2016.12.009","article-title":"Patients with hypertension-associated thrombotic microangiopathy may present with complement abnormalities.","volume":"916","author":"Timmermans","year":"2017","journal-title":"Kidney Int."},{"key":"B26","doi-asserted-by":"publisher","first-page":"2228","DOI":"10.1016\/j.molimm.2006.11.012","article-title":"Classical pathway complement activation on human endothelial cells.","volume":"449","author":"Yin","year":"2007","journal-title":"Mol Immunol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"3493","DOI":"10.1093\/ndt\/gfr811","article-title":"Arteriolar vascular smooth muscle cell differentiation in benign nephrosclerosis.","volume":"279","author":"Bockmeyer","year":"2012","journal-title":"Nephrol Dial Transplant."},{"key":"B28","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1038\/ajh.2011.214","article-title":"Role of complement 3a in the synthetic phenotype and angiotensin II-production in vascular smooth muscle cells from spontaneously hypertensive rats.","volume":"253","author":"Han","year":"2012","journal-title":"Am J Hypertens."}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2022.836155\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,31]],"date-time":"2022-03-31T09:47:40Z","timestamp":1648720060000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2022.836155\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,31]]},"references-count":28,"alternative-id":["10.3389\/fmed.2022.836155"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2022.836155","relation":{},"ISSN":["2296-858X"],"issn-type":[{"type":"electronic","value":"2296-858X"}],"subject":[],"published":{"date-parts":[[2022,3,31]]},"article-number":"836155"}}