{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T21:26:47Z","timestamp":1768512407252,"version":"3.49.0"},"posted":{"date-parts":[[2024,5,15]]},"group-title":"Pathology","reference-count":55,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,5,15]],"date-time":"2024-05-15T00:00:00Z","timestamp":1715731200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,9,27]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Pharmacological inhibition of megalin (also known as low-density lipoprotein receptor-related protein 2: LRP2) attenuates atherosclerosis in hypercholesterolemic mice. Since megalin is abundant in renal proximal tubule cells (PTCs), the purpose of this study was to determine whether PTC-specific deletion of megalin reduces hypercholesterolemia-induced atherosclerosis in mice.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    Female\n                    <jats:italic>Lrp2<\/jats:italic>\n                    f\/f mice were bred with male\n                    <jats:italic>Ndrg1<\/jats:italic>\n                    -\n                    <jats:italic>Cre ERT2<\/jats:italic>\n                    +\/0 mice to develop PTC-LRP2 +\/+ and \u2212\/\u2212 littermates. To study atherosclerosis, all mice were bred to an LDL receptor \u2212\/\u2212 background and fed a Western diet to induce atherosclerosis.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>PTC-specific megalin deletion did not attenuate atherosclerosis in LDL receptor \u2212\/\u2212 mice in either sex. Serendipitously, we discovered that PTC-specific megalin deletion led to interstitial infiltration of CD68+ cells and tubular atrophy. The pathology was only evident in male PTC-LRP2 \u2212\/\u2212 mice fed the Western diet, but not in mice fed a normal laboratory diet. Renal pathologies were also observed in male PTC-LRP2 \u2212\/\u2212 mice in an LDL receptor +\/+ background fed the same Western diet, demonstrating that the renal pathologies were dependent on diet and not hypercholesterolemia. In contrast, female PTC-LRP2 \u2212\/\u2212 mice had no apparent renal pathologies. In vivo multiphoton microscopy demonstrated that PTC-specific megalin deletion dramatically diminished albumin accumulation in PTCs within 10 days of Western diet feeding. RNA sequencing analyses demonstrated the upregulation of inflammation-related pathways in kidney.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>PTC-specific megalin deletion does not affect atherosclerosis, but leads to tubulointerstitial nephritis in mice fed Western diet, with severe pathologies in male mice.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2024.05.11.592234","type":"posted-content","created":{"date-parts":[[2024,5,15]],"date-time":"2024-05-15T11:05:19Z","timestamp":1715771119000},"source":"Crossref","is-referenced-by-count":0,"title":["Renal Proximal Tubule Cell-specific Megalin Deletion Does Not Affect Atherosclerosis But Induces Tubulointerstitial Nephritis in Mice Fed Western Diet"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5732-1951","authenticated-orcid":false,"given":"Naofumi","family":"Amioka","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4993-0164","authenticated-orcid":false,"given":"Michael K.","family":"Franklin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8393-9333","authenticated-orcid":false,"given":"Masayoshi","family":"Kukida","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1702-1118","authenticated-orcid":false,"given":"Liyuan","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2556-6719","authenticated-orcid":false,"given":"Jessica 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