{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T09:03:10Z","timestamp":1789549390698,"version":"build-2803163510"},"reference-count":56,"publisher":"Portland Press Ltd.","issue":"10","license":[{"start":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T00:00:00Z","timestamp":1788393600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000925","name":"DHAC | National Health and Medical Research Council","doi-asserted-by":"publisher","award":["2012552"],"award-info":[{"award-number":["2012552"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,10,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Senescent cell accumulation and fibrosis play a fundamental role in kidney ageing. Our aim was to determine whether the angiotensin IV\/insulin-regulated aminopeptidase (IRAP) axis of the renin-angiotensin system contributes to renal function decline, fibrosis, and senescent cell accumulation in aged mice. We studied the role of IRAP in kidney ageing using IRAP knockout (KO) mice, as well as in wild-type (WT) mice treated with an IRAP inhibitor. Complementary proximal tubule and collecting duct cell models were used to determine the mechanisms by which IRAP inhibition exerts protective effects. Glomerular filtration rate (GFR) declined by 25% in WT mice between 3 and 23\u00a0months of age, concomitant with marked increases in albumin excretion, glomerulosclerosis, tubulointerstitial fibrosis, and accumulation of senescent cells in the proximal tubules of the kidney. IRAP KO mice were protected against age-related decline in GFR, renal fibrosis, and senescence burden compared with age-matched WT mice. IRAP inhibition for 4\u00a0weeks (HFI-419, 500\u00a0ng\/kg\/min) in 28-month-old WT mice similarly prevented age-related decline in GFR and attenuated expression of cellular senescence markers. Using an in vitro model of cultured proximal tubule cells, IRAP inhibition mitigated the pro-senescent effects of oxidative stress. This was associated with shifts in the metabolic phenotype of proximal tubular cells, indicating the senoprotective effects of IRAP inhibition may be mediated in part via mitochondrial function. These studies provide evidence that IRAP deficiency is protective against chronic renal cellular senescence, fibrosis, and functional decline. Therefore, IRAP inhibition has therapeutic potential to attenuate pathological cardiorenal ageing through senoprotective mechanisms.<\/jats:p>","DOI":"10.1042\/cs20261576","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T13:38:13Z","timestamp":1788442693000},"page":"2035-2051","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["IRAP deficiency preserves renal function and attenuates pathology in aged mice"],"prefix":"10.1042","volume":"140","author":[{"given":"Sarah\u00a0L.","family":"Walton","sequence":"first","affiliation":[{"name":"1Department of Physiology, Monash University, Clayton, Victoria, Australia"},{"name":"2Cardiovascular Disease Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aneesa","family":"Ansari","sequence":"additional","affiliation":[{"name":"1Department of Physiology, Monash University, Clayton, Victoria, Australia"},{"name":"2Cardiovascular Disease Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katrina\u00a0M.","family":"Mirabito Colafella","sequence":"additional","affiliation":[{"name":"1Department of Physiology, Monash University, Clayton, Victoria, Australia"},{"name":"2Cardiovascular Disease Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucinda\u00a0M.","family":"Hilliard Krause","sequence":"additional","affiliation":[{"name":"1Department of Physiology, Monash University, Clayton, Victoria, Australia"},{"name":"2Cardiovascular Disease Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giannie","family":"Barsha","sequence":"additional","affiliation":[{"name":"1Department of Physiology, Monash University, Clayton, Victoria, Australia"},{"name":"2Cardiovascular Disease Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle\u00a0M.","family":"Kett","sequence":"additional","affiliation":[{"name":"1Department of Physiology, Monash University, Clayton, Victoria, Australia"},{"name":"6Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siew\u00a0Yeen","family":"Chai","sequence":"additional","affiliation":[{"name":"1Department of Physiology, Monash University, Clayton, Victoria, Australia"},{"name":"3Neuroscience Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vesna\u00a0D.","family":"Garovic","sequence":"additional","affiliation":[{"name":"4Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, U.S.A."},{"name":"5Division of Nephrology and Hypertension, Mayo Clinic, Rochester, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5929-4387","authenticated-orcid":false,"given":"Kate\u00a0M.","family":"Denton","sequence":"additional","affiliation":[{"name":"1Department of Physiology, Monash University, Clayton, Victoria, Australia"},{"name":"2Cardiovascular Disease Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2026,9,16]]},"reference":[{"key":"2026091604064952800_B1","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1038\/nrneph.2017.189","article-title":"Sex-specific differences in hypertension and associated cardiovascular disease","volume":"14","author":"Colafella","year":"2018","journal-title":"Nat. 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