{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T08:48:46Z","timestamp":1790498926454,"version":"4.1.0"},"reference-count":124,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["DK-44863"],"award-info":[{"award-number":["DK-44863"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["DK-90728"],"award-info":[{"award-number":["DK-90728"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000871","name":"Mayo Clinic","doi-asserted-by":"publisher","award":["91384127"],"award-info":[{"award-number":["91384127"]}],"id":[{"id":"10.13039\/100000871","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Blueprint Medicines Inc","award":["91384148"],"award-info":[{"award-number":["91384148"]}]}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["JASN"],"published-print":{"date-parts":[[2022,6]]},"abstract":"\n Significance Statement<\/jats:title>\n \n The only treatment approved for PKD inhibits production of cAMP, the main PKA activator. It is only partially effective, likely because side effects restrict dosing and because other sources of cAMP and mechanisms of cAMP-independent PKA activation exist. Which PKA isozyme(s) promotes PKD is uncertain and selective PKA inhibitors usable\n in vivo<\/jats:italic>\n have not been available. Experiments in a mouse model show PKA-I is the main PKA isozyme promoting cystogenesis and that constitutive PKA-I downregulation and a novel, highly selective PKA inhibitor ameliorate PKD. The dose of PKA inhibitor used had no detectable adverse effects. This information provides a strong rationale for a strategy that may be more effective, or substantially increase the efficacy of the currently approved treatment.\n <\/jats:p>\n <\/jats:sec>\n \n Background<\/jats:title>\n \n Upregulation of cAMP-dependent and cAMP-independent PKA signaling is thought to promote cystogenesis in polycystic kidney disease (PKD). PKA-I regulatory subunit RI\n \u03b1<\/jats:italic>\n is increased in kidneys of orthologous mouse models. Kidney-specific knockout of RI\n \u03b1<\/jats:italic>\n upregulates PKA activity, induces cystic disease in wild-type mice, and aggravates it in\n Pkd1<\/jats:italic>\n RC\/RC<\/jats:sup>\n mice.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n PKA-I activation or inhibition was compared with EPAC activation or PKA-II inhibition using\n Pkd1<\/jats:italic>\n RC\/RC<\/jats:sup>\n metanephric organ cultures. The effect of constitutive PKA (preferentially PKA-I) downregulation\n in vivo<\/jats:italic>\n was ascertained by kidney-specific expression of a dominant negative\n RI\u03b1B<\/jats:italic>\n allele in\n Pkd1<\/jats:italic>\n RC\/RC<\/jats:sup>\n mice obtained by crossing\n Prkar1\u03b1<\/jats:italic>\n R1\u03b1B\/WT<\/jats:sup>\n ,\n Pkd1RC\/RC<\/jats:italic>\n , and\n Pkhd1-<\/jats:italic>\n Cre mice (C57BL\/6 background). The effect of pharmacologic PKA inhibition using a novel, selective PRKACA inhibitor (BLU2864) was tested in mIMCD3 3D cultures, metanephric organ cultures, and\n Pkd1RC\/RC<\/jats:italic>\n mice on a C57BL\/6\u2009\u00d7\u2009129S6\/Sv F1 background. Mice were sacrificed at 16 weeks of age.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n PKA-I activation promoted and inhibition prevented\n ex vivo<\/jats:italic>\n P-Ser133 CREB expression and cystogenesis. EPAC activation or PKA-II inhibition had no or only minor effects. BLU2864 inhibited\n in vitro<\/jats:italic>\n mIMCD3 cystogenesis and\n ex vivo<\/jats:italic>\n P-Ser133 CREB expression and cystogenesis. Genetic downregulation of PKA activity and BLU2864 directly and\/or indirectly inhibited many pro-proliferative pathways and were both protective\n in vivo<\/jats:italic>\n . BLU2864 had no detectable on- or off-target adverse effects.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n PKA-I is the main PKA isozyme promoting cystogenesis. Direct PKA inhibition may be an effective strategy to treat PKD and other conditions where PKA signaling is upregulated. By acting directly on PKA, the inhibition may be more effective than or substantially increase the efficacy of treatments that only affect PKA activity by lowering cAMP.<\/jats:p>\n <\/jats:sec>","DOI":"10.1681\/asn.2021081125","type":"journal-article","created":{"date-parts":[[2022,3,2]],"date-time":"2022-03-02T14:10:19Z","timestamp":1646230219000},"page":"1087-1104","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":26,"title":["Protein Kinase A Downregulation Delays the Development and Progression of Polycystic Kidney Disease"],"prefix":"10.1681","volume":"33","author":[{"given":"Xiaofang","family":"Wang","sequence":"first","affiliation":[{"name":"Division of Nephrology and Hypertension and Robert M. and Billie Kelley Pirnie Translational PKD Center, Mayo Clinic, Rochester, Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Jiang","sequence":"additional","affiliation":[{"name":"Division of Nephrology and Hypertension and Robert M. and Billie Kelley Pirnie Translational PKD Center, Mayo Clinic, Rochester, Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ka","family":"Thao","sequence":"additional","affiliation":[{"name":"Division of Nephrology and Hypertension and Robert M. and Billie Kelley Pirnie Translational PKD Center, Mayo Clinic, Rochester, Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3965-256X","authenticated-orcid":false,"given":"Caroline R.","family":"Sussman","sequence":"additional","affiliation":[{"name":"Division of Nephrology and Hypertension and Robert M. and Billie Kelley Pirnie Translational PKD Center, Mayo Clinic, Rochester, Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy","family":"LaBranche","sequence":"additional","affiliation":[{"name":"Blueprint Medicines, Cambridge, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Palmer","sequence":"additional","affiliation":[{"name":"Blueprint Medicines, Cambridge, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5304-6593","authenticated-orcid":false,"given":"Peter C.","family":"Harris","sequence":"additional","affiliation":[{"name":"Division of Nephrology and Hypertension and Robert M. and Billie Kelley Pirnie Translational PKD Center, Mayo Clinic, Rochester, Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G. Stanley","family":"McKnight","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Washington, Seattle, Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus P.","family":"Hoeflich","sequence":"additional","affiliation":[{"name":"Blueprint Medicines, Cambridge, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie","family":"Schalm","sequence":"additional","affiliation":[{"name":"Blueprint Medicines, Cambridge, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vicente E.","family":"Torres","sequence":"additional","affiliation":[{"name":"Division of Nephrology and Hypertension and Robert M. and Billie Kelley Pirnie Translational PKD Center, Mayo Clinic, Rochester, Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2022,6]]},"reference":[{"key":"B2-20240826","doi-asserted-by":"crossref","first-page":"1993","DOI":"10.1016\/S0140-6736(15)60907-2","article-title":"Autosomal dominant polycystic kidney disease: The changing face of clinical management","volume":"385","author":"Ong","year":"2015","journal-title":"Lancet"},{"key":"B3-20240826","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1038\/ki.2015.59","article-title":"Autosomal-dominant polycystic kidney disease (ADPKD): Executive summary from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference","volume":"88","author":"Chapman","year":"2015","journal-title":"Kidney Int"},{"key":"B4-20240826","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1038\/s41572-018-0047-y","article-title":"Polycystic kidney disease","volume":"4","author":"Bergmann","year":"2018","journal-title":"Nat Rev Dis Primers"},{"key":"B5-20240826","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1016\/S0140-6736(18)32782-X","article-title":"Autosomal dominant polycystic kidney disease","volume":"393","author":"Cornec-Le Gall","year":"2019","journal-title":"Lancet"},{"key":"B6-20240826","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1038\/nm935","article-title":"Inhibition of renal cystic disease development and progression by a vasopressin V2 receptor antagonist","volume":"9","author":"Gattone","year":"2003","journal-title":"Nat Med"},{"key":"B7-20240826","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1038\/nm1004","article-title":"Effective treatment of an orthologous model of autosomal dominant polycystic kidney disease","volume":"10","author":"Torres","year":"2004","journal-title":"Nat Med"},{"key":"B8-20240826","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1681\/ASN.2004121090","article-title":"Effectiveness of vasopressin V2 receptor antagonists OPC-31260 and OPC-41061 on polycystic kidney disease development in the PCK rat","volume":"16","author":"Wang","year":"2005","journal-title":"J Am Soc Nephrol"},{"key":"B9-20240826","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1681\/ASN.2007060688","article-title":"Vasopressin directly regulates cyst growth in polycystic kidney disease","volume":"19","author":"Wang","year":"2008","journal-title":"J Am Soc Nephrol"},{"key":"B10-20240826","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1124\/jpet.114.213256","article-title":"Tolvaptan delays the onset of end-stage renal disease in a polycystic kidney disease model by suppressing increases in kidney volume and renal injury","volume":"349","author":"Aihara","year":"2014","journal-title":"J Pharmacol Exp Ther"},{"key":"B11-20240826","doi-asserted-by":"crossref","first-page":"2407","DOI":"10.1056\/NEJMoa1205511","article-title":"Tolvaptan in patients with autosomal dominant polycystic kidney disease","volume":"367","author":"Torres","year":"2012","journal-title":"N Engl J Med"},{"key":"B12-20240826","doi-asserted-by":"crossref","first-page":"1930","DOI":"10.1056\/NEJMoa1710030","article-title":"Tolvaptan in later-stage autosomal dominant polycystic kidney disease","volume":"377","author":"Torres","year":"2017","journal-title":"N Engl J Med"},{"key":"B13-20240826","doi-asserted-by":"crossref","first-page":"2458","DOI":"10.1681\/ASN.2018060590","article-title":"A practical guide for treatment of rapidly progressive ADPKD with tolvaptan","volume":"29","author":"Chebib","year":"2018","journal-title":"J Am Soc Nephrol"},{"key":"B14-20240826","doi-asserted-by":"crossref","first-page":"110992","DOI":"10.1016\/j.mce.2020.110992","article-title":"Everything you ever wanted to know about PKA regulation and its involvement in mammalian sperm capacitation","volume":"518","author":"Baro Graf","year":"2020","journal-title":"Mol Cell Endocrinol"},{"key":"B15-20240826","first-page":"D678","article-title":"Specificity in the cAMP\/PKA signaling pathway. 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