{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T01:51:11Z","timestamp":1785376271576,"version":"3.55.0"},"posted":{"date-parts":[[2026,4,14]]},"group-title":"Physiology","reference-count":33,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T00:00:00Z","timestamp":1776124800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"crossref","award":["R01DK124901"],"award-info":[{"award-number":["R01DK124901"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000050","name":"National Heart Lung and Blood Institute","doi-asserted-by":"crossref","award":["R01HL132318"],"award-info":[{"award-number":["R01HL132318"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000050","name":"National Heart Lung and Blood Institute","doi-asserted-by":"crossref","award":["R01HL1157069"],"award-info":[{"award-number":["R01HL1157069"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,13]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Dysregulation of phosphate homeostasis contributes to reduced longevity and vascular complications in chronic kidney disease and aging. This study investigates the role of TMEM174, a proximal tubule-specific protein, in regulating the phosphate co-transporter NPT2A and its subsequent impact on lifespan and vascular health.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>TMEM174 knockout (KO) mice (C57BL6\/J and DBA\/2J) were fed diets with varying phosphate concentrations (0.6% vs. 1.2%). In OKP cells, TIRF and FRET microscopy, alongside immunoprecipitation, were used to identify the TMEM174 protein regions essential for NPT2A binding and endocytosis.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>TMEM174 KO mice exhibited significantly shorter lifespans than wild-type controls. High phosphate diets exacerbated vascular calcification, stiffness, and mortality, while low phosphate diets rescued these phenotypes. In vitro, TMEM174 siRNA blocked PTH-induced NPT2A endocytosis, increasing its apical membrane retention. FRET and biochemical assays revealed that the C-terminal region of TMEM174 is essential for its association with NPT2A. While intact TMEM174 and N-terminal mutants (TMEM174\u0394N) facilitated NPT2A degradation, C-terminal deletions (TMEM174\u0394C) failed to associate with or degrade NPT2A.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>TMEM174 is a critical regulator of phosphate homeostasis and longevity. The C-terminal region of TMEM174 is specifically required for NPT2A endocytosis and degradation, identifying it as a potential therapeutic target for managing phosphate-related vascular complications.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.04.09.716713","type":"posted-content","created":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T15:40:19Z","timestamp":1776181219000},"source":"Crossref","is-referenced-by-count":1,"title":["TMEM174 Deficiency Reduces Longevity by Promoting Phosphate-Driven Vascular Calcification"],"prefix":"10.64898","author":[{"given":"Jose G","family":"Miranda","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, CO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judith","family":"Blaine","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, CO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makoto","family":"Miyazaki","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, CO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"issue":"8","key":"2026041707200791000_2026.04.09.716713v1.1","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1038\/s41581-019-0159-y","article-title":"Mechanisms of phosphate transport","volume":"15","year":"2019","journal-title":"Nat Rev 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unrecognized internal NPT2A PDZ motif disrupt phosphate transport and cause congenital hypophosphatemia","volume":"480","year":"2023","journal-title":"Biochem J"},{"issue":"5","key":"2026041707200791000_2026.04.09.716713v1.10","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1097\/MNH.0000000000000828","article-title":"Sodium phosphate cotransporter 2a inhibitors: potential therapeutic uses","volume":"31","year":"2022","journal-title":"Curr Opin Nephrol 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