{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,10]],"date-time":"2026-01-10T03:40:02Z","timestamp":1768016402107,"version":"3.49.0"},"reference-count":38,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,9,6]],"date-time":"2017-09-06T00:00:00Z","timestamp":1504656000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,9,6]],"date-time":"2017-09-06T00:00:00Z","timestamp":1504656000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Increased proteinuria causes tubulointerstitial injury due to inflammation in chronic kidney disease (CKD). Iron restriction exhibits protective effects against renal dysfunction; however, its effects against protein overload-induced tubulointerstitial damage remain unclear. Here, we investigated dietary iron restriction effect on tubulointerstitial damage in mice with protein-overload tubulointerstitial injury. Renal tubulointerstitial injury in animal model was induced by intraperitoneal injection of an overdose of bovine serum albumin (BSA). We divided mice into three groups: normal saline\u2009+\u2009normal diet (ND), BSA\u2009+\u2009ND, and BSA\u2009+\u2009iron-restricted diet (IRD). BSA overload induced renal tubulointerstitial injury in the ND mice, which was ameliorated in the IRD mice. Inflammatory cytokines and extracellular matrix mRNA expression was upregulated in BSA\u2009+\u2009ND mice kidneys and was inhibited by IRD. BSA-induced increase in renal superoxide production, NADPH oxidase activity, and p22<jats:sup>phox<\/jats:sup> expression was diminished in the IRD mice. IRD suppression increased BSA-induced renal macrophage infiltration. Moreover, BSA mice exhibited nucleotide-binding oligomerisation domain-like receptor pyrin domain-containing protein (NLRP) inflammasome activation, which was inhibited by IRD. Ferrous iron increased in kidneys with BSA overload and was inhibited by IRD. Thus, iron restriction inhibited oxidative stress and inflammatory changes, contributing to the protective effect against BSA overload-induced tubulointerstitial injury.<\/jats:p>","DOI":"10.1038\/s41598-017-11089-0","type":"journal-article","created":{"date-parts":[[2017,8,31]],"date-time":"2017-08-31T09:16:13Z","timestamp":1504170973000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Dietary iron restriction alleviates renal tubulointerstitial injury induced by protein overload in mice"],"prefix":"10.1038","volume":"7","author":[{"given":"Yasumasa","family":"Ikeda","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuya","family":"Horinouchi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hirofumi","family":"Hamano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tasuku","family":"Hirayama","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seiji","family":"Kishi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8178-9028","authenticated-orcid":false,"given":"Yuki","family":"Izawa-Ishizawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masaki","family":"Imanishi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7879-423X","authenticated-orcid":false,"given":"Yoshito","family":"Zamami","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenshi","family":"Takechi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Licht","family":"Miyamoto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keisuke","family":"Ishizawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ken-ichi","family":"Aihara","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hideko","family":"Nagasawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Koichiro","family":"Tsuchiya","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toshiaki","family":"Tamaki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2017,9,6]]},"reference":[{"key":"11089_CR1","doi-asserted-by":"publisher","first-page":"765","DOI":"10.1016\/S0272-6386(96)90512-0","volume":"27","author":"C Burton","year":"1996","unstructured":"Burton, C. & Harris, K. P. The role of proteinuria in the progression of chronic renal failure. American journal of kidney diseases: the official journal of the National Kidney Foundation \n                           27, 765\u2013775 (1996).","journal-title":"American journal of kidney diseases: the official journal of the National Kidney Foundation"},{"key":"11089_CR2","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1093\/ndt\/gfg533","volume":"19","author":"AA Eddy","year":"2004","unstructured":"Eddy, A. A. Proteinuria and interstitial injury. Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association - European Renal Association \n                           19, 277\u2013281 (2004).","journal-title":"Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association - European Renal Association"},{"key":"11089_CR3","doi-asserted-by":"publisher","first-page":"1115","DOI":"10.1681\/ASN.2009070760","volume":"21","author":"X Li","year":"2010","unstructured":"Li, X. et al. PKC-delta promotes renal tubular cell apoptosis associated with proteinuria. 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Kidney international \n                           61, 2066\u20132077, doi:10.1046\/j.1523-1755.2002.00380.x (2002).","journal-title":"Kidney international"},{"key":"11089_CR6","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1159\/000098432","volume":"27","author":"AT Whaley-Connell","year":"2007","unstructured":"Whaley-Connell, A. T. et al. Albumin activation of NAD(P)H oxidase activity is mediated via Rac1 in proximal tubule cells. American journal of nephrology \n                           27, 15\u201323, doi:10.1159\/000098432 (2007).","journal-title":"American journal of nephrology"},{"key":"11089_CR7","doi-asserted-by":"publisher","first-page":"25101","DOI":"10.1074\/jbc.M114.578260","volume":"289","author":"Y Zhuang","year":"2014","unstructured":"Zhuang, Y. et al. NLRP3 inflammasome mediates albumin-induced renal tubular injury through impaired mitochondrial function. The Journal of biological chemistry \n                           289, 25101\u201325111, doi:10.1074\/jbc.M114.578260 (2014).","journal-title":"The Journal of biological chemistry"},{"key":"11089_CR8","doi-asserted-by":"publisher","first-page":"1293","DOI":"10.1038\/aps.2014.66","volume":"35","author":"LH Ding","year":"2014","unstructured":"Ding, L. H. et al. Enalapril inhibits tubulointerstitial inflammation and NLRP3 inflammasome expression in BSA-overload nephropathy of rats. Acta pharmacologica Sinica \n                           35, 1293\u20131301, doi:10.1038\/aps.2014.66 (2014).","journal-title":"Acta pharmacologica Sinica"},{"key":"11089_CR9","doi-asserted-by":"crossref","unstructured":"Kruszewski, M. Labile iron pool: the main determinant of cellular response to oxidative stress. Mutat Res \n                           531, 81\u201392, doi:S0027510703001623 [pii] (2003).","DOI":"10.1016\/j.mrfmmm.2003.08.004"},{"key":"11089_CR10","doi-asserted-by":"crossref","unstructured":"Cairo, G., Recalcati, S., Pietrangelo, A. & Minotti, G. The iron regulatory proteins: targets and modulators of free radical reactions and oxidative damage. Free Radic Biol Med \n                           32, 1237\u20131243, doi:S0891584902008250 [pii] (2002).","DOI":"10.1016\/S0891-5849(02)00825-0"},{"key":"11089_CR11","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1038\/nrneph.2013.98","volume":"9","author":"AM Martines","year":"2013","unstructured":"Martines, A. M. et al. Iron metabolism in the pathogenesis of iron-induced kidney injury. Nature reviews. Nephrology \n                           9, 385\u2013398, doi:10.1038\/nrneph.2013.98 (2013).","journal-title":"Nature reviews. 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European journal of pharmacology \n                           756, 85\u201391, doi:10.1016\/j.ejphar.2015.03.053 (2015).","journal-title":"European journal of pharmacology"},{"key":"11089_CR14","doi-asserted-by":"publisher","first-page":"1156","DOI":"10.3109\/0886022X.2013.819729","volume":"35","author":"M Matsumoto","year":"2013","unstructured":"Matsumoto, M. et al. Iron restriction prevents diabetic nephropathy in Otsuka Long-Evans Tokushima fatty rat. Renal failure \n                           35, 1156\u20131162, doi:10.3109\/0886022X.2013.819729 (2013).","journal-title":"Renal failure"},{"key":"11089_CR15","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1291\/hypres.27.599","volume":"27","author":"K Saito","year":"2004","unstructured":"Saito, K. et al. Role of aberrant iron homeostasis in the upregulation of transforming growth factor-beta1 in the kidney of angiotensin II-induced hypertensive rats. Hypertension research: official journal of the Japanese Society of Hypertension \n                           27, 599\u2013607 (2004).","journal-title":"Hypertension research: official journal of the Japanese Society of Hypertension"},{"key":"11089_CR16","doi-asserted-by":"publisher","first-page":"2192","DOI":"10.1097\/HJH.0b013e3283581a64","volume":"30","author":"Y Naito","year":"2012","unstructured":"Naito, Y. et al. Effect of iron restriction on renal damage and mineralocorticoid receptor signaling in a rat model of chronic kidney disease. Journal of hypertension \n                           30, 2192\u20132201, doi:10.1097\/HJH.0b013e3283581a64 (2012).","journal-title":"Journal of hypertension"},{"key":"11089_CR17","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0089355","volume":"9","author":"Y Ikeda","year":"2014","unstructured":"Ikeda, Y. et al. Iron chelation by deferoxamine prevents renal interstitial fibrosis in mice with unilateral ureteral obstruction. 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Experimental hematology \n                           44, 116\u2013124, doi:10.1016\/j.exphem.2015.11.002 (2016).","journal-title":"Experimental hematology"},{"key":"11089_CR28","doi-asserted-by":"publisher","first-page":"1686","DOI":"10.1016\/j.celrep.2015.05.023","volume":"11","author":"BD Gelfand","year":"2015","unstructured":"Gelfand, B. D. et al. Iron Toxicity in the Retina Requires Alu RNA and the NLRP3 Inflammasome. Cell reports \n                           11, 1686\u20131693, doi:10.1016\/j.celrep.2015.05.023 (2015).","journal-title":"Cell reports"},{"key":"11089_CR29","doi-asserted-by":"publisher","first-page":"616","DOI":"10.1002\/eji.200940168","volume":"40","author":"F Martinon","year":"2010","unstructured":"Martinon, F. Signaling by ROS drives inflammasome activation. 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