{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T22:43:00Z","timestamp":1781649780017,"version":"3.54.5"},"reference-count":73,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2021,3,17]],"date-time":"2021-03-17T00:00:00Z","timestamp":1615939200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["DK102043"],"award-info":[{"award-number":["DK102043"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000124","name":"Office of Research on Women's Health","doi-asserted-by":"publisher","award":["DK102043S1"],"award-info":[{"award-number":["DK102043S1"]}],"id":[{"id":"10.13039\/100000124","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000052","name":"NIH Office of the Director","doi-asserted-by":"publisher","award":["DK102043S2"],"award-info":[{"award-number":["DK102043S2"]}],"id":[{"id":"10.13039\/100000052","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Proximal tubular (PT) acidosis, which alkalinizes the urinary filtrate, together with Ca2+ supersaturation in PT can induce luminal calcium phosphate (CaP) crystal formation. While such CaP crystals are known to act as a nidus for CaP\/calcium oxalate (CaOx) mixed stone formation, the regulation of PT luminal Ca2+ concentration ([Ca2+]) under elevated pH and\/or high [Ca2+] conditions are unknown. Since we found that transient receptor potential canonical 3 (TRPC3) knockout (KO; -\/-) mice could produce mild hypercalciuria with CaP urine crystals, we alkalinized the tubular pH in TRPC3-\/- mice by oral acetazolamide (0.08%) to develop mixed urinary crystals akin to clinical signs of calcium nephrolithiasis (CaNL). Our ratiometric (\u03bb340\/380) intracellular [Ca2+] measurements reveal that such alkalization not only upsurges Ca2+ influx into PT cells, but the mode of Ca2+ entry switches from receptor-operated to store-operated pathway. Electrophysiological experiments show enhanced bicarbonate related current activity in treated PT cells which may determine the stone-forming phenotypes (CaP or CaP\/CaOx). Moreover, such alkalization promotes reactive oxygen species generation, and upregulation of calcification, inflammation, fibrosis, and apoptosis in PT cells, which were exacerbated in absence of TRPC3. Altogether, the pH-induced alteration of the Ca2+ signaling signature in PT cells from TRPC3 ablated mice exacerbated the pathophysiology of mixed urinary stone formation, which may aid in uncovering the downstream mechanism of CaNL.<\/jats:p>","DOI":"10.3390\/ijms22063050","type":"journal-article","created":{"date-parts":[[2021,3,17]],"date-time":"2021-03-17T05:43:26Z","timestamp":1615959806000},"page":"3050","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Modulation of Tubular pH by Acetazolamide in a Ca2+ Transport Deficient Mice Facilitates Calcium Nephrolithiasis"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2858-4875","authenticated-orcid":false,"given":"Eugenia","family":"Awuah Boadi","sequence":"first","affiliation":[{"name":"Calcium Signaling Laboratory, Research Service, Veterans Affairs Medical Center, 50 Irving Street, NW, Washington, DC 20422, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel","family":"Shin","sequence":"additional","affiliation":[{"name":"Calcium Signaling Laboratory, Research Service, Veterans Affairs Medical Center, 50 Irving Street, NW, Washington, DC 20422, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel","family":"Yeroushalmi","sequence":"additional","affiliation":[{"name":"Calcium Signaling Laboratory, Research Service, Veterans Affairs Medical Center, 50 Irving Street, NW, Washington, DC 20422, USA"},{"name":"Division of Renal Diseases &amp; Hypertension, Department of Medicine, The George Washington University, Washington, DC 20037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bok-Eum","family":"Choi","sequence":"additional","affiliation":[{"name":"Calcium Signaling Laboratory, Research Service, Veterans Affairs Medical Center, 50 Irving Street, NW, Washington, DC 20422, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peijun","family":"Li","sequence":"additional","affiliation":[{"name":"Calcium Signaling Laboratory, Research Service, Veterans Affairs Medical Center, 50 Irving Street, NW, Washington, DC 20422, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2364-8945","authenticated-orcid":false,"given":"Bidhan C.","family":"Bandyopadhyay","sequence":"additional","affiliation":[{"name":"Calcium Signaling Laboratory, Research Service, Veterans Affairs Medical Center, 50 Irving Street, NW, Washington, DC 20422, USA"},{"name":"Division of Renal Diseases &amp; Hypertension, Department of Medicine, The George Washington University, Washington, DC 20037, USA"},{"name":"Department of Biomedical Engineering, The Catholic University of America, 620 Michigan Avenue NE, Washington, DC 20064, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2160","DOI":"10.1097\/01.ASN.0000023430.92674.E5","article-title":"Renal tubular acidosis: The clinical entity","volume":"13","year":"2002","journal-title":"J. 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