{"doi":"10.3410/f.737844929.793575466","title":"Faculty Opinions recommendation of A novel role of LRP5 in tubulointerstitial fibrosis through activating TGF-β/Smad signaling.","abstract":"Previous studies by us and others demonstrated that activation of Wnt/-catenin signaling plays a pathogenic role in chronic kidney diseases (CKD). Wnt co-receptor LRP5 variants are reported to associate with autosomal dominant polycystic kidney disease; but their exact roles in this disease and renal fibrosis have not been explored. Here, we observed the upregulation of LRP5 in the renal tubules of both type 1 and type 2 diabetic models and of an obstructive nephropathy model. In the obstructed kidneys, Lrp5 knockout significantly ameliorated tubulointerstitial fibrosis and tubular injury without changing Wnt/-catenin signaling. Instead, decreased levels of TGF-1 and TGF- receptors (TRs) were detected in Lrp5 knockout kidneys, followed by attenuated activation and nuclear translocation of Smad2/3 in the renal tubules, suggesting a regulatory effect of LRP5 on TGF-/Smad signaling. In consistent with this hypothesis, LRP5 overexpression resulted in enhanced TGF-/Smad signaling activation in renal tubule epithelial cells. Furthermore, LRP5 was co-immunoprecipitated with TRI and TRII, and its extracellular domain was essential for interacting with TRs and for its pro-fibrotic activity. In addition to stabilizing TRs, LRP5 increased the basal membrane presentation and TGF-1-induced internalization of these receptors. Notably, TGF-1 also induced LRP5 internalization. These findings indicate that LRP5 promotes tubulointerstitial fibrosis, at least partially, via direct modulation of TGF-/Smad signaling, a novel, Wnt-independent function.","journal":"Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature","year":2020,"id":133483,"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":0.9533,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":589600,"name":"Ciara Ross","orcid":null,"position":1,"is_corresponding":false},{"id":589004,"name":"Derek P. Brazil","orcid":"0000-0003-1375-1076","position":0,"is_corresponding":true}],"reference_count":25,"raw_metadata":null,"created_at":"2026-07-18T23:16:17.577688Z","pmid":null,"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":[]}