{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T13:16:16Z","timestamp":1788441376174,"version":"build-2803163510"},"reference-count":37,"publisher":"IMR Press","issue":"8","license":[{"start":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T00:00:00Z","timestamp":1786924800000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Front. Biosci. (Landmark Ed)"],"abstract":"<jats:p>Background:Calcium oxalate (CaOx) crystal retention on the renal tubular epithelium is a key step in urolithiasis. Phosphatidylserine (PS) exposure may facilitate crystal\u2013cell adhesion, but the upstream signaling mechanisms and the relative contributions of impaired inward PS flipping versus outward PS redistribution remain unclear.Materials and Methods:Global proteomic profiling using 2-dimensional electrophoresis and matrix-assisted laser desorption\/ionization time-of-flight\/time-of-flight mass spectrometry (2-DE\/MALDI-TOF\/TOF) in an immortalized human proximal tubular epithelial cell line (HK-2) cells exposed to calcium oxalate monohydrate (COM) identified upregulation of the calcium-sensing receptor (CaSR). HK-2 cells were treated with COM with or without the CaSR antagonist NPS2390 or the CaSR agonist gadolinium chloride (GdCl3). Bidirectional PS transport was assessed using an N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) (NBD)-labeled phosphatidylserine (NBD-PS) fluorescence-quenching assay, and surface PS exposure was measured by annexin V binding. Aminophospholipid translocase (APLT) expression, APLT-dependent inward PS transport, crystal adhesion, oxidative stress, and apoptosis-related signaling were evaluated.Results:COM increased CaSR expression, enhanced surface PS exposure, and promoted crystal adhesion with concurrent oxidative stress and apoptosis-related signaling. COM induced a CaSR-sensitive defect in APLT-dependent inward PS flipping: NPS2390 partially restored inward PS transport and APLT expression, whereas GdCl3 exacerbated these changes. In contrast, COM-enhanced outward PS redistribution and externalization was largely unaffected by CaSR modulation, indicating relative CaSR insensitivity of the outward process. Consistently, CaSR activation aggravated, while CaSR inhibition attenuated, crystal adhesion and injury-related readouts.Conclusions:COM was associated with enhanced crystal\u2013cell adhesion, CaSR activation, and a CaSR-sensitive impairment of APLT-dependent inward PS flipping, whereas enhanced outward PS redistribution appeared largely CaSR-insensitive. Pharmacologic inhibition of CaSR attenuated epithelial injury and crystal retention-related readouts, suggesting that CaSR may represent a potential therapeutic target.<\/jats:p>","DOI":"10.31083\/fbl53201","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T12:35:31Z","timestamp":1788438931000},"source":"Crossref","is-referenced-by-count":0,"title":["Calcium-Sensing Receptor Activation Disrupts Phosphatidylserine Asymmetry and Promotes Calcium Oxalate Crystal\u2013Induced Epithelial Injury in Renal Tubular Epithelial Cells"],"prefix":"10.31083","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-3096-3756","authenticated-orcid":true,"given":"Hanlin","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Urology, The Second Hospital & Clinical Medical School, Lanzhou University, 730000 Lanzhou, Gansu, China"},{"name":"Institute of Urology, Gansu Province Clinical Research Center for Urinary System Diseases, The Second Hospital of Lanzhou University, 730030 Lanzhou, Gansu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8144-0257","authenticated-orcid":true,"given":"Yangjie","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Urology, The Second Hospital & Clinical Medical School, Lanzhou University, 730000 Lanzhou, Gansu, China"},{"name":"Institute of Urology, Gansu Province Clinical Research Center for Urinary System Diseases, The Second Hospital of Lanzhou University, 730030 Lanzhou, Gansu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuqiang","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Urology, The Second Hospital & Clinical Medical School, Lanzhou University, 730000 Lanzhou, Gansu, China"},{"name":"Institute of Urology, Gansu Province Clinical Research Center for Urinary System Diseases, The Second Hospital of Lanzhou University, 730030 Lanzhou, Gansu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyu","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Urology, The Second Hospital & Clinical Medical School, Lanzhou University, 730000 Lanzhou, Gansu, China"},{"name":"Institute of Urology, Gansu Province Clinical Research Center for Urinary System Diseases, The Second Hospital of Lanzhou University, 730030 Lanzhou, Gansu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Urology, The Second Hospital & Clinical Medical School, Lanzhou University, 730000 Lanzhou, Gansu, China"},{"name":"Institute of Urology, Gansu Province Clinical Research Center for Urinary System Diseases, The Second Hospital of Lanzhou University, 730030 Lanzhou, Gansu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1336-2476","authenticated-orcid":true,"given":"Xiaoran","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Urology, The Second Hospital & Clinical Medical School, Lanzhou University, 730000 Lanzhou, Gansu, China"},{"name":"Institute of Urology, Gansu Province Clinical Research Center for Urinary System Diseases, The Second Hospital of Lanzhou University, 730030 Lanzhou, Gansu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2026,8,17]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Bamberger JN, Blum KA, Kan KM, Parkhomenko E, Gallante B, Gupta M. 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