{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T15:07:42Z","timestamp":1780672062179,"version":"3.54.1"},"reference-count":35,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2019,12,25]],"date-time":"2019-12-25T00:00:00Z","timestamp":1577232000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["15K12749"],"award-info":[{"award-number":["15K12749"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["23111004"],"award-info":[{"award-number":["23111004"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["23659102"],"award-info":[{"award-number":["23659102"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Renal proximal tubular epithelial cells are significantly damaged during acute kidney injury. Renal proximal tubular cell-specific autophagy-deficient mice show increased sensitivity against renal injury, while showing few pathological defects under normal fed conditions. Considering that autophagy protects the proximal tubular cells from acute renal injury, it is reasonable to assume that autophagy contributes to the maintenance of renal tubular cells under normal fed conditions. To clarify this possibility, we generated a knock out mouse model which lacks Atg7, a key autophagosome forming enzyme, in renal proximal tubular cells (Atg7flox\/flox;KAP-Cre+). Analysis of renal tissue from two months old Atg7flox\/flox;KAP-Cre+ mouse revealed an accumulation of LC3, binding protein p62\/sequestosome 1 (a selective substrate for autophagy), and more interestingly, Kim-1, a biomarker for early kidney injury, in the renal proximal tubular cells under normal fed conditions. TUNEL (TdT-mediated dUTP Nick End Labeling)-positive cells were also detected in the autophagy-deficient renal tubular cells. Analysis of renal tissue from Atg7flox\/flox;KAP-Cre+ mice at different age points showed that tubular cells positive for p62 and Kim-1 continually increase in number in an age-dependent manner. Ultrastructural analysis of tubular cells from Atg7flox\/flox;KAP-Cre+ revealed the presence of intracellular inclusions and abnormal structures. These results indicated that autophagy-deficiency in the renal proximal epithelial tubular cells leads to an increase in injured cells in the kidney even under normal fed conditions.<\/jats:p>","DOI":"10.3390\/ijms21010155","type":"journal-article","created":{"date-parts":[[2019,12,25]],"date-time":"2019-12-25T11:07:48Z","timestamp":1577272068000},"page":"155","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Autophagy Deficiency in Renal Proximal Tubular Cells Leads to an Increase in Cellular Injury and Apoptosis under Normal Fed Conditions"],"prefix":"10.3390","volume":"21","author":[{"given":"Chigure","family":"Suzuki","sequence":"first","affiliation":[{"name":"Department of Cellular and Molecular Neuropathology, Juntendo University Graduate School of Medicine, Bunkyo-Ku, Tokyo 113-8421, Japan"},{"name":"Department of Cellular and Molecular Pharmacology, Juntendo University Graduate School of Medicine, Bunkyo-Ku, Tokyo 113-8421, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isei","family":"Tanida","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Neuropathology, Juntendo University Graduate School of Medicine, Bunkyo-Ku, Tokyo 113-8421, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Alejandro","family":"Oliva Trejo","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Neuropathology, Juntendo University Graduate School of Medicine, Bunkyo-Ku, Tokyo 113-8421, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soichiro","family":"Kakuta","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Neuropathology, Juntendo University Graduate School of Medicine, Bunkyo-Ku, Tokyo 113-8421, Japan"},{"name":"Laboratory of Morphology and Image Analysis, Biomedical Research Center, Juntendo University Graduate School of Medicine, Bunkyo-Ku, Tokyo 113-8421, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuo","family":"Uchiyama","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Neuropathology, Juntendo University Graduate School of Medicine, Bunkyo-Ku, Tokyo 113-8421, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,12,25]]},"reference":[{"key":"ref_1","first-page":"414","article-title":"Structural and functional features of protein handling in the kidney proximal tubule","volume":"11","author":"Christensen","year":"1991","journal-title":"Semin. Nephrol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1038\/ki.1979.128","article-title":"Renal filtration, transport, and metabolism of low-molecular-weight proteins: A review","volume":"16","author":"Maack","year":"1979","journal-title":"Kidney Int."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Suzuki, C., Tanida, I., Ohmuraya, M., Oliva Trejo, J.A., Kakuta, S., Sunabori, T., and Uchiyama, Y. (2019). Lack of Cathepsin D in the Renal Proximal Tubular Cells Resulted in Increased Sensitivity against Renal Ischemia\/Reperfusion Injury. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20071711"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.1093\/ndt\/gft510","article-title":"A basic science view of acute kidney injury biomarkers","volume":"29","author":"Charlton","year":"2014","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1046\/j.1523-1755.2002.00433.x","article-title":"Kidney Injury Molecule-1 (KIM-1): A novel biomarker for human renal proximal tubule injury","volume":"62","author":"Han","year":"2002","journal-title":"Kidney Int."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.4161\/auto.19821","article-title":"Emerging role of autophagy in kidney function, diseases and aging","volume":"8","author":"Huber","year":"2012","journal-title":"Autophagy"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"F244","DOI":"10.1152\/ajprenal.00033.2009","article-title":"Autophagy: Molecular machinery, regulation, and implications for renal pathophysiology","volume":"297","author":"Jiang","year":"2009","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1146\/annurev-genet-102808-114910","article-title":"Regulation mechanisms and signaling pathways of autophagy","volume":"43","author":"He","year":"2009","journal-title":"Annu. Rev. Genet"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1038\/35056522","article-title":"Molecular dissection of autophagy: Two ubiquitin-like systems","volume":"2","author":"Ohsumi","year":"2001","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2503","DOI":"10.1016\/j.biocel.2004.05.009","article-title":"LC3 conjugation system in mammalian autophagy","volume":"36","author":"Tanida","year":"2004","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/S1937-6448(07)66005-5","article-title":"New insights into the mechanisms of macroautophagy in mammalian cells","volume":"266","author":"Eskelinen","year":"2008","journal-title":"Int. Rev. Cell Mol. Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1701","DOI":"10.1074\/jbc.C000752200","article-title":"The human homolog of Saccharomyces cerevisiae Apg7p is a Protein-activating enzyme for multiple substrates including human Apg12p, GATE-16, GABARAP, and MAP-LC3","volume":"276","author":"Tanida","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"13739","DOI":"10.1074\/jbc.M200385200","article-title":"Human Apg3p\/Aut1p homologue is an authentic E2 enzyme for multiple substrates, GATE-16, GABARAP, and MAP-LC3, and facilitates the conjugation of hApg12p to hApg5p","volume":"277","author":"Tanida","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3017","DOI":"10.1074\/jbc.M505888200","article-title":"Phosphatidylserine in addition to phosphatidylethanolamine is an in vitro target of the mammalian Atg8 modifiers, LC3, GABARAP, and GATE-16","volume":"281","author":"Sou","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"5720","DOI":"10.1093\/emboj\/19.21.5720","article-title":"LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing","volume":"19","author":"Kabeya","year":"2000","journal-title":"EMBO J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/15548627.2015.1100356","article-title":"Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)","volume":"12","author":"Klionsky","year":"2016","journal-title":"Autophagy"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1080\/15548627.2016.1166317","article-title":"Persistent activation of autophagy in kidney tubular cells promotes renal interstitial fibrosis during unilateral ureteral obstruction","volume":"12","author":"Livingston","year":"2016","journal-title":"Autophagy"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1038\/ki.2012.261","article-title":"Autophagy in proximal tubules protects against acute kidney injury","volume":"82","author":"Jiang","year":"2012","journal-title":"Kidney Int."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"22171","DOI":"10.1038\/srep22171","article-title":"Autophagy is activated to protect against endotoxic acute kidney injury","volume":"6","author":"Mei","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"28142","DOI":"10.1074\/jbc.272.44.28142","article-title":"The kidney androgen-regulated protein promoter confers renal proximal tubule cell-specific and highly androgen-responsive expression on the human angiotensinogen gene in transgenic mice","volume":"272","author":"Ding","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1083\/jcb.200412022","article-title":"Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice","volume":"169","author":"Komatsu","year":"2005","journal-title":"J. Cell Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1080\/15548627.2016.1159376","article-title":"Time-dependent dysregulation of autophagy: Implications in aging and mitochondrial homeostasis in the kidney proximal tubule","volume":"12","author":"Yamamoto","year":"2016","journal-title":"Autophagy"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1016\/j.cell.2007.10.035","article-title":"Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice","volume":"131","author":"Komatsu","year":"2007","journal-title":"Cell"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"902","DOI":"10.1681\/ASN.2010070705","article-title":"Autophagy protects the proximal tubule from degeneration and acute ischemic injury","volume":"22","author":"Kimura","year":"2011","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1038\/ki.2011.120","article-title":"Apoptosis and acute kidney injury","volume":"80","author":"Havasi","year":"2011","journal-title":"Kidney Int."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1038\/nmeth.2089","article-title":"NIH Image to ImageJ: 25 years of image analysis","volume":"9","author":"Schneider","year":"2012","journal-title":"Nat. Methods"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"6898","DOI":"10.1523\/JNEUROSCI.20-18-06898.2000","article-title":"Cathepsin D deficiency induces lysosomal storage with ceroid lipofuscin in mouse CNS neurons","volume":"20","author":"Koike","year":"2000","journal-title":"J. Neurosci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1769","DOI":"10.1681\/ASN.2012111080","article-title":"Obesity-mediated autophagy insufficiency exacerbates proteinuria-induced tubulointerstitial lesions","volume":"24","author":"Yamahara","year":"2013","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"826","DOI":"10.4161\/auto.19419","article-title":"Autophagy plays a critical role in kidney tubule maintenance, aging and ischemia-reperfusion injury","volume":"8","author":"Liu","year":"2012","journal-title":"Autophagy"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1016\/j.ajpath.2011.11.001","article-title":"Autophagy guards against cisplatin-induced acute kidney injury","volume":"180","author":"Takahashi","year":"2012","journal-title":"Am. J. Pathol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2199","DOI":"10.1097\/01.ASN.0000079785.13922.F6","article-title":"Recent advances in the pathophysiology of ischemic acute renal failure","volume":"14","author":"Bonventre","year":"2003","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1016\/j.stem.2008.01.014","article-title":"Intrinsic epithelial cells repair the kidney after injury","volume":"2","author":"Humphreys","year":"2008","journal-title":"Cell Stem Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"228","DOI":"10.14336\/AD.2014.0917","article-title":"Increasing Proliferation of Intrinsic Tubular Cells after Renal Ischemia-reperfusion Injury in Adult Rat","volume":"6","author":"Feng","year":"2015","journal-title":"Aging Dis."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1681\/ASN.2011121159","article-title":"Liver angiotensinogen is the primary source of renal angiotensin II","volume":"23","author":"Matsusaka","year":"2012","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1713","DOI":"10.1016\/S0002-9440(10)61253-9","article-title":"Participation of autophagy in storage of lysosomes in neurons from mouse models of neuronal ceroid-lipofuscinoses (Batten disease)","volume":"167","author":"Koike","year":"2005","journal-title":"Am. J. Pathol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/1\/155\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:45:30Z","timestamp":1760190330000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/1\/155"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,12,25]]},"references-count":35,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,1]]}},"alternative-id":["ijms21010155"],"URL":"https:\/\/doi.org\/10.3390\/ijms21010155","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,12,25]]}}}