{"doi":"10.1101/2024.05.11.592234","title":"Renal Proximal Tubule Cell-specific Megalin Deletion Does Not Affect Atherosclerosis But Induces Tubulointerstitial Nephritis in Mice Fed Western Diet","abstract":"Background: 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. Methods: +/0 mice to develop PTC-LRP2 +/+ and -/- littermates. To study atherosclerosis, all mice were bred to an LDL receptor -/- background and fed a Western diet to induce atherosclerosis. Results: PTC-specific megalin deletion did not attenuate atherosclerosis in LDL receptor -/- 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 -/- mice fed the Western diet, but not in mice fed a normal laboratory diet. Renal pathologies were also observed in male PTC-LRP2 -/- 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 -/- 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. Conclusions: PTC-specific megalin deletion does not affect atherosclerosis, but leads to tubulointerstitial nephritis in mice fed Western diet, with severe pathologies in male mice.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":497596,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9592,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":711798,"name":"Michael Franklin","orcid":"0000-0003-4993-0164","position":1,"is_corresponding":false},{"id":711795,"name":"Masayoshi Kukida","orcid":"0000-0002-8393-9333","position":2,"is_corresponding":false},{"id":1307996,"name":"Liyuan Zhu","orcid":"0000-0003-1702-1118","position":3,"is_corresponding":false},{"id":920827,"name":"Jessica J. Moorleghen","orcid":"0000-0002-2556-6719","position":4,"is_corresponding":false},{"id":469842,"name":"Deborah A. Howatt","orcid":"0000-0002-0078-092X","position":5,"is_corresponding":false},{"id":244994,"name":"Yuriko Katsumata","orcid":"0000-0002-0188-8094","position":6,"is_corresponding":false},{"id":321595,"name":"Adam E. Mullick","orcid":"0000-0003-4600-961X","position":7,"is_corresponding":false},{"id":1028559,"name":"Motoko Yanagita","orcid":"0000-0002-0339-9008","position":8,"is_corresponding":false},{"id":1344491,"name":"Michelle M Martinez-Irizarry","orcid":null,"position":9,"is_corresponding":false},{"id":846226,"name":"Ruben M. Sandoval","orcid":"0000-0002-3660-2092","position":10,"is_corresponding":false},{"id":374826,"name":"Kenneth W. Dunn","orcid":"0000-0003-4245-496X","position":11,"is_corresponding":false},{"id":536586,"name":"Hisashi Sawada","orcid":"0000-0003-0017-6236","position":12,"is_corresponding":false},{"id":232109,"name":"Alan Daugherty","orcid":"0000-0003-2093-3775","position":13,"is_corresponding":false},{"id":103409,"name":"Hong Lü","orcid":"0000-0002-0577-2558","position":14,"is_corresponding":false},{"id":1140797,"name":"Naofumi Amioka","orcid":"0000-0002-5732-1951","position":0,"is_corresponding":true}],"reference_count":56,"raw_metadata":null,"created_at":"2026-07-19T02:09:34.764412Z","pmid":"38798535","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}