{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T00:47:19Z","timestamp":1792802839943,"version":"4.5.0"},"reference-count":37,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","funder":[{"name":"National Institutes of Health\/National Institute of Diabetes and Digestive Kidney Diseases","award":["R01 DK54053"],"award-info":[{"award-number":["R01 DK54053"]}],"id":[{"id":"https:\/\/ror.org\/00adh9b73","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Institutes of Health\/National Institute of Diabetes and Digestive Kidney Diseases","award":["DK100592"],"award-info":[{"award-number":["DK100592"]}],"id":[{"id":"https:\/\/ror.org\/00adh9b73","id-type":"ROR","asserted-by":"crossref"}]},{"DOI":"10.13039\/100001296","name":"PKD Foundation","doi-asserted-by":"crossref","award":["202g16a"],"award-info":[{"award-number":["202g16a"]}],"id":[{"id":"10.13039\/100001296","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["JASN"],"published-print":{"date-parts":[[2023,1]]},"abstract":"\n Significance Statement<\/jats:title>\n \n XBP1 activation in neonatal and adult doxycycline-inducible murine models of ADPKD due to a hypomorphic polycystin-1 missense mutation orthologous to human PC1R2220W delays cyst formation. Activating XBP1s, a pro-chaperone inducer of the endoplasmic reticulum stress response, can improve steady-state expression, ciliary trafficking, and cleavage of the mutant protein, providing initial\n in vivo<\/jats:italic>\n proof of concept that modulating levels of poorly functioning hypomorphic PC1 alleles can slow progression of kidney cyst formation in ADPKD.\n <\/jats:p>\n <\/jats:sec>\n \n Background<\/jats:title>\n \n Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in\n Pkd1<\/jats:italic>\n and\n Pkd2.<\/jats:italic>\n They encode the polytopic integral membrane proteins polycystin-1 (PC1) and polycystin-2 (PC2), respectively, which are expressed on primary cilia. Formation of kidney cysts in ADPKD starts when a somatic second hit mechanism inactivates the wild-type Pkd allele. Approximately one quarter of families with ADPDK due to\n Pkd1<\/jats:italic>\n have germline nonsynonymous amino acid substitution (missense) mutations. A subset of these mutations is hypomorphic, retaining some residual PC1 function. Previous studies have shown that the highly conserved Ire1\n \u03b1<\/jats:italic>\n -XBP1 pathway of the unfolded protein response can modulate levels of functional PC1 in the presence of mutations in genes required for post-translational maturation of integral membrane proteins. We examine how activity of the endoplasmic reticulum chaperone-inducing transcription factor XBP1 affects ADPKD in a murine model with missense\n Pkd1<\/jats:italic>\n .\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n We engineered a\n Pkd1<\/jats:italic>\n REJ domain missense murine model,\n Pkd1R2216W<\/jats:italic>\n , on the basis of the orthologous human hypomorphic allele\n Pkd1R2220W<\/jats:italic>\n , and examined the effects of transgenic activation of XBP1 on ADPKD progression.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Expression of active XBP1 in cultured cells bearing PC1\n R2216W<\/jats:sup>\n mutations increased levels and ciliary trafficking of PC1\n R2216W<\/jats:sup>\n . Mice homozygous for\n Pkd1R2216W<\/jats:italic>\n or heterozygous for\n Pkd1R2216W<\/jats:italic>\n in trans<\/jats:italic>\n with a conditional\n Pkd1fl<\/jats:italic>\n allele exhibit severe ADPKD following inactivation in neonates or adults. Transgenic expression of spliced XBP1 in tubule segments destined to form cysts reduced cell proliferation and improved Pkd progression, according to structural and functional parameters.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n Modulating ER chaperone function through XBP1 activity improved Pkd in a murine model of PC1, suggesting therapeutic targeting of hypomorphic mutations.<\/jats:p>\n <\/jats:sec>","DOI":"10.1681\/asn.2021091180","type":"journal-article","created":{"date-parts":[[2022,10,31]],"date-time":"2022-10-31T08:25:38Z","timestamp":1667204738000},"page":"110-121","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":20,"title":["XBP1 Activation Reduces Severity of Polycystic Kidney Disease due to a Nontruncating Polycystin-1 Mutation in Mice"],"prefix":"10.1681","volume":"34","author":[{"given":"Matteus","family":"Krappitz","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Section of Nephrology, Yale School of Medicine, New Haven, Connecticut"},{"name":"Department of Nephrology and Medical Intensive Care, Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, Berlin, Germany"},{"name":"BIH Biomedical Innovation Academy, Berlin Institute of Health at Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rishi","family":"Bhardwaj","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Section of Nephrology, Yale School of Medicine, New Haven, Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Section of Nephrology, Yale School of Medicine, New Haven, Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7825-2385","authenticated-orcid":false,"given":"Tobias","family":"Staudner","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Section of Nephrology, Yale School of Medicine, New Haven, Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duygu Elif","family":"Yilmaz","sequence":"additional","affiliation":[{"name":"Department of Nephrology and Medical Intensive Care, Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlotta","family":"Pioppini","sequence":"additional","affiliation":[{"name":"Department of Nephrology and Medical Intensive Care, Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Parisa","family":"Westergerling","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Section of Nephrology, Yale School of Medicine, New Haven, Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Ruemmele","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Section of Nephrology, Yale School of Medicine, New Haven, Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Till","family":"Hollmann","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Section of Nephrology, Yale School of Medicine, New Haven, Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6913-1928","authenticated-orcid":false,"given":"Thuy Anh","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, 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