{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T08:52:49Z","timestamp":1776761569929,"version":"3.51.2"},"reference-count":32,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,1,4]],"date-time":"2022-01-04T00:00:00Z","timestamp":1641254400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:p>Renal tubulointerstitial fibrosis is a common pathological feature of progressive chronic kidney disease (CKD), and current treatment has limited efficacy. The circular RNA circHIPK3 is reported to participate in the pathogenesis of various human diseases. However, the role of circHIPK3 in renal fibrosis has not been examined. In this study, we aimed to determine whether and how circHIPK3 might participate in the pathogenesis of renal fibrosis. Mice received a peritoneal injection of folic acid (250 mg\/kg). Of note, 30 days later, renal fibrosis was present on periodic acid\u2013Schiff (PAS) and Masson staining, and mRNA and protein of profibrotic genes encoding fibronectin (FN) and collagen 1 (COL1) were increased. Renal circHIPK3 was upregulated, while miR-30a was downregulated, assessed by quantitative PCR (qPCR) and fluorescence <jats:italic>in situ<\/jats:italic> hybridization (FISH). The expression of transforming growth factor beta-1 (TGF-\u03b21) was increased by qPCR analysis, immunoblotting, and immunofluorescence. Renal circHIPK3 negatively correlated with miR-30a, and kidney miR-30a negatively correlated with TGF-\u03b21. Target Scan and miRanda algorithms predicted three perfect binding sites between circHIPK3 and miR-30a. We found that circHIPK3, miR-30a, and TGF-\u03b21 colocalized in the cytoplasm of human tubular epithelial cells (HK-2 cells) on FISH and immunofluorescence staining. We transfected circHIPK3 and a scrambled RNA into HK-2 cells; miR-30a was downregulated, and the profibrotic genes such as TGF-\u03b21, FN, and COL1 were upregulated and assessed by qPCR, immunoblotting, and immunofluorescence staining. Third, the upregulation of circHIPK3, downregulation of miR-30a, and overproduction of profibrotic FN and COL1 were also observed in HK-2 cells exposed to TGF-\u03b21. Finally, renal biopsies from patients with chronic tubulointerstitial nephritis manifested similar expression patterns of circHIPK3, miR-30a, and profibrotic proteins, such as TGF-\u03b21, FN, and COL1 as observed in the experimental model. A feed-forward cycle was observed among circHIPK3, miR-30a, and TGF-\u03b21. Our results suggest that circHIPK3 may contribute to progressive renal fibrosis by sponging miR-30a. circHIPK3 may be a novel therapeutic target for slowing CKD progression.<\/jats:p>","DOI":"10.3389\/fphys.2021.715567","type":"journal-article","created":{"date-parts":[[2022,1,4]],"date-time":"2022-01-04T05:19:51Z","timestamp":1641273591000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":18,"title":["circHIPK3 Exacerbates Folic Acid-Induced Renal Tubulointerstitial Fibrosis by Sponging miR-30a"],"prefix":"10.3389","volume":"12","author":[{"given":"Yan","family":"Wu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junjun","family":"Luan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Congcong","family":"Jiao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shiwen","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cong","family":"Ma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yixiao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingqi","family":"Fu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"En Yin","family":"Lai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffrey B.","family":"Kopp","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingbo","family":"Pi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hua","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,1,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-020-03169-3","article-title":"Exosomal circ_DLGAP4 promotes diabetic kidney disease progression by sponging miR-143 and targeting ERBB3\/NF-\u03baB\/MMP-2 axis.","volume":"11","author":"Bai","year":"2020","journal-title":"Cell Death Dis."},{"key":"B2","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1016\/j.canlet.2017.10.019","article-title":"TGF-\u03b21 targets a microRNA network that regulates cellular adhesion and migration in renal cancer.","volume":"412","author":"Bogus\u0142awska","year":"2018","journal-title":"Cancer Lett."},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3390\/cells8020177","article-title":"Circular RNA circHIPK3 promotes the proliferation and differentiation of chicken myoblast cells by sponging miR-30a-3p.","volume":"8","author":"Chen","year":"2019","journal-title":"Cells"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-017-0204-3","article-title":"circHIPK3 regulates cell proliferation and migration by sponging miR-124 and regulating AQP3 expression in hepatocellular carcinoma.","volume":"9","author":"Chen","year":"2018","journal-title":"Cell Death Dis."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1294","DOI":"10.1001\/jama.2019.14745","article-title":"Chronic Kidney disease diagnosis and management: a review.","volume":"322","author":"Chen","year":"2019","journal-title":"JAMA"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-016-0370-2","article-title":"Circular RNAs in cancer: an emerging key player.","volume":"10","author":"Dong","year":"2017","journal-title":"J. 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