{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T01:48:46Z","timestamp":1787017726347,"version":"build-2736575974"},"reference-count":48,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2021,6,23]],"date-time":"2021-06-23T00:00:00Z","timestamp":1624406400000},"content-version":"vor","delay-in-days":173,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005925","name":"Buddhist Tzu Chi Medical Foundation","doi-asserted-by":"publisher","award":["109-2320-B-303-004-MY3"],"award-info":[{"award-number":["109-2320-B-303-004-MY3"]}],"id":[{"id":"10.13039\/501100005925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005925","name":"Buddhist Tzu Chi Medical Foundation","doi-asserted-by":"publisher","award":["TCRD-TPE-109-06"],"award-info":[{"award-number":["TCRD-TPE-109-06"]}],"id":[{"id":"10.13039\/501100005925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008108","name":"Taipei Tzu Chi Hospital","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100008108","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Oxidative Medicine and Cellular Longevity"],"published-print":{"date-parts":[[2021,1]]},"abstract":"<jats:p>\n                    Previous studies have shown that mutations in the tumor suppressor gene von Hippel\u2010Lindau (\n                    <jats:italic>VHL<\/jats:italic>\n                    ) can result in the overproduction of reactive oxygen species (ROS) and chronic inflammation and are a significant predisposing factor for the development of clear\u2010cell renal cell carcinoma (ccRCC). To study VHL\u2019s role in ccRCC formation, we previously developed a novel conditional knockout mouse model that mimicked the features of kidney inflammation and fibrosis that lead to cyst formation and hyperplasia. However, due to VHL\u2019s complex cellular functions, the mechanism of this phenomenon remains unclear. Here, we used the HK\u20102 cells and mouse primary renal tubule cells (mRTCs) carrying\n                    <jats:italic>VHL<\/jats:italic>\n                    mutations as models to study the effects and underlying molecular mechanisms of ROS accumulation. We also studied the role of lipocalin 2 (LCN2) in regulating macrophage recruitment by HK\u20102 cells. We measured the level of ROS in HK\u20102 cells in the presence or absence of LCN2 knockdown and found that the\n                    <jats:italic>VHL<\/jats:italic>\n                    mutation caused ROS overproduction, but an LCN2 knockdown could attenuate the process. VHL was also found to mediate the\n                    <jats:italic>in vitro<\/jats:italic>\n                    and\n                    <jats:italic>in vivo<\/jats:italic>\n                    expression and secretion of LCN2. Thus, VHL likely affects ROS production in an LCN2\u2010dependent manner. Our findings also suggest that LCN2 sensitizes the inflammatory response of HK\u20102 cells and the chemotactic abilities of macrophage RAW264.7 cells. By demonstrating that the loss of function of von Hippel\u2010Lindau triggers lipocalin 2\u2010dependent inflammatory responses in cultured and primary renal tubular cells, our results offer novel insights into a potential therapeutic approach for interfering with the development of ccRCC.\n                  <\/jats:p>","DOI":"10.1155\/2021\/5571638","type":"journal-article","created":{"date-parts":[[2021,6,23]],"date-time":"2021-06-23T14:20:09Z","timestamp":1624458009000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Loss of Function of von Hippel\u2010Lindau Trigger Lipocalin 2\u2010Dependent Inflammatory Responses in Cultured and Primary Renal Tubular Cells"],"prefix":"10.1155","volume":"2021","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5702-5730","authenticated-orcid":false,"given":"Chan-Yen","family":"Kuo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Chiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Po-Chun","family":"Hsieh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tien","family":"Hsu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting-Yun","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,6,23]]},"reference":[{"key":"e_1_2_9_1_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra043172"},{"key":"e_1_2_9_2_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2004.05.061"},{"key":"e_1_2_9_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2014.197"},{"key":"e_1_2_9_4_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-16-3196"},{"key":"e_1_2_9_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2010.07.016"},{"key":"e_1_2_9_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00980-14"},{"key":"e_1_2_9_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature01322"},{"key":"e_1_2_9_8_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-0348-0837-8_9"},{"key":"e_1_2_9_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1535-6108(02)00071-5"},{"key":"e_1_2_9_10_2","first-page":"2827","article-title":"Identification of the MN\/CA9 protein as a reliable diagnostic biomarker of clear cell carcinoma of the kidney","volume":"57","author":"Liao S. 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