{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T11:48:11Z","timestamp":1791978491675,"version":"4.4.0"},"reference-count":78,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2018,10,17]],"date-time":"2018-10-17T00:00:00Z","timestamp":1539734400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2019,1]]},"abstract":"<jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>\n                            Significant and selective up\u2010regulation of the Na\n                            <jats:sup>+<\/jats:sup>\n                            \/H\n                            <jats:sup>+<\/jats:sup>\n                            exchanger NHA2 (\n                            <jats:italic>SLC9B2<\/jats:italic>\n                            ) was observed in cysts of patients with autosomal dominant polycystic kidney disease.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            Using the MDCK cell model of cystogenesis, it was found that NHA2 increases cyst size. Silencing or pharmacological inhibition of NHA2 inhibits cyst formation\n                            <jats:italic>in\u00a0vitro<\/jats:italic>\n                            .\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            Polycystin\u20101 represses NHA2 expression via Ca\n                            <jats:sup>2+<\/jats:sup>\n                            \/NFAT signalling whereas the dominant negative membrane\u2010anchored C\u2010terminal fragment (PC1\u2010MAT) increased NHA2 levels.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Drugs (caffeine, theophylline) and hormones (vasopressin, aldosterone) known to exacerbate cysts elicit NHA2 expression.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Taken together, the findings reveal NHA2 as a potential new player in salt and water homeostasis in the kidney and in the pathogenesis of polycystic kidney disease.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>\n                      Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in\n                      <jats:italic>PKD1<\/jats:italic>\n                      and\n                      <jats:italic>PKD2<\/jats:italic>\n                      encoding polycystin\u20101 (PC1) and polycystin\u20102 (PC2), respectively. The molecular pathways linking polycystins to cyst development in ADPKD are still unclear. Intracystic fluid secretion via ion transporters and channels plays a crucial role in cyst expansion in ADPKD. Unexpectedly, we observed significant and selective up\u2010regulation of NHA2, a member of the\n                      <jats:italic>SLC9B<\/jats:italic>\n                      family of Na\n                      <jats:sup>+<\/jats:sup>\n                      \/H\n                      <jats:sup>+<\/jats:sup>\n                      exchangers, that correlated with cyst size and disease severity in ADPKD patients. Using three\u2010dimensional cultures of MDCK cells to model cystogenesis\n                      <jats:italic>in\u00a0vitro<\/jats:italic>\n                      , we showed that ectopic expression of NHA2 is causal to increased cyst size. Induction of PC1 in MDCK cells inhibited NHA2 expression with concordant inhibition of Ca\n                      <jats:sup>2+<\/jats:sup>\n                      influx through store\u2010dependent and \u2010independent pathways, whereas reciprocal activation of Ca\n                      <jats:sup>2+<\/jats:sup>\n                      influx by the dominant negative membrane\u2010anchored C\u2010terminal tail fragment of PC1 elevated NHA2. We showed that NHA2 is a target of Ca\n                      <jats:sup>2+<\/jats:sup>\n                      \/NFAT signalling and is transcriptionally induced by methylxanthine drugs such as caffeine and theophylline, which are contraindicated in ADPKD patients. Finally, we observed robust induction of NHA2 by vasopressin, which is physiologically consistent with increased levels of circulating vasopressin and up\u2010regulation of vasopressin V2 receptors in ADPKD. Our findings have mechanistic implications on the emerging use of vasopressin V2 receptor antagonists such as tolvaptan as safe and effective therapy for polycystic kidney disease and reveal a potential new regulator of transepithelial salt and water transport in the kidney.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1113\/jp276796","type":"journal-article","created":{"date-parts":[[2018,9,22]],"date-time":"2018-09-22T09:16:47Z","timestamp":1537607807000},"page":"499-519","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["NHA2 promotes cyst development in an\n                    <i>in\u00a0vitro<\/i>\n                    model of polycystic kidney disease"],"prefix":"10.1113","volume":"597","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0486-1919","authenticated-orcid":false,"given":"Hari","family":"Prasad","sequence":"first","affiliation":[{"name":"Department of Physiology Johns Hopkins University School of Medicine  Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donna K.","family":"Dang","sequence":"additional","affiliation":[{"name":"Department of Physiology Johns Hopkins University School of Medicine  Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kalyan C.","family":"Kondapalli","sequence":"additional","affiliation":[{"name":"Department of Physiology Johns Hopkins University School of Medicine  Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niranjana","family":"Natarajan","sequence":"additional","affiliation":[{"name":"Department of Physiology Johns Hopkins University School of Medicine  Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeriu","family":"Cebotaru","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Maryland School of Medicine  Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1833-5971","authenticated-orcid":false,"given":"Rajini","family":"Rao","sequence":"additional","affiliation":[{"name":"Department of Physiology Johns Hopkins University School of Medicine  Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,10,17]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2184.2008.00529.x"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI35711"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.563817"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.11.6013"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00070.2012"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.ASN.0000025282.48298.7B"},{"key":"e_1_2_5_8_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2164-10-233"},{"key":"e_1_2_5_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/11.8.923"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2011.01.033"},{"key":"e_1_2_5_11_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0911987106"},{"key":"e_1_2_5_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-011-0967-9"},{"key":"e_1_2_5_13_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.501205"},{"key":"e_1_2_5_14_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199010183231602"},{"key":"e_1_2_5_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2012.08.113"},{"key":"e_1_2_5_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrneph.2015.39"},{"key":"e_1_2_5_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2016.65"},{"key":"e_1_2_5_18_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00188.2014"},{"key":"e_1_2_5_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00233310"},{"key":"e_1_2_5_20_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00330.2013"},{"key":"e_1_2_5_21_1","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.111.199539"},{"key":"e_1_2_5_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.24702"},{"key":"e_1_2_5_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mam.2012.05.001"},{"key":"e_1_2_5_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.08.040"},{"key":"e_1_2_5_25_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-013-1408-8"},{"key":"e_1_2_5_26_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2007111245"},{"key":"e_1_2_5_27_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI37873"},{"key":"e_1_2_5_28_1","doi-asserted-by":"publisher","DOI":"10.2165\/00023210-200923050-00004"},{"key":"e_1_2_5_29_1","doi-asserted-by":"publisher","DOI":"10.2215\/CJN.00330705"},{"key":"e_1_2_5_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrneph.2010.18"},{"key":"e_1_2_5_31_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M212388200"},{"key":"e_1_2_5_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng0695-151"},{"key":"e_1_2_5_33_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.8.4947"},{"key":"e_1_2_5_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms6482"},{"key":"e_1_2_5_35_1","doi-asserted-by":"publisher","DOI":"10.11005\/jbm.2014.21.4.233"},{"key":"e_1_2_5_36_1","first-page":"123","article-title":"Dietary sodium intake increases vasopressin secretion in man","volume":"1","author":"Kjeldsen SE","year":"1985","journal-title":"J\u00a0Clin Hypertens"},{"key":"e_1_2_5_37_1","first-page":"526","article-title":"Effects of long\u2010term lithium administration on renal structure and function in rats. A distinctive tubular lesion","volume":"50","author":"Kling MA","year":"1984","journal-title":"Lab Invest"},{"key":"e_1_2_5_38_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10517-018-4074-1"},{"key":"e_1_2_5_39_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.403550"},{"key":"e_1_2_5_40_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2014.00172"},{"key":"e_1_2_5_41_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13105-016-0539-8"},{"key":"e_1_2_5_42_1","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20080489"},{"key":"e_1_2_5_43_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.76.3.1323"},{"key":"e_1_2_5_44_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI107317"},{"key":"e_1_2_5_45_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00438-017-1381-6"},{"key":"e_1_2_5_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2015.01.006"},{"key":"e_1_2_5_47_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.73.4.1212"},{"key":"e_1_2_5_48_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.440050306"},{"key":"e_1_2_5_49_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi035074c"},{"key":"e_1_2_5_50_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00382685"},{"key":"e_1_2_5_51_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00063.2011"},{"key":"e_1_2_5_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(15)60907-2"},{"key":"e_1_2_5_53_1","doi-asserted-by":"publisher","DOI":"10.2174\/1566524011313040007"},{"key":"e_1_2_5_54_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkq267"},{"key":"e_1_2_5_55_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0447.1984.tb02527.x"},{"key":"e_1_2_5_56_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA118.002025"},{"key":"e_1_2_5_57_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M402905200"},{"key":"e_1_2_5_58_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng0697-179"},{"key":"e_1_2_5_59_1","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.jbchem.a122445"},{"key":"e_1_2_5_60_1","doi-asserted-by":"publisher","DOI":"10.1038\/ki.1992.37"},{"key":"e_1_2_5_61_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2008080882"},{"key":"e_1_2_5_62_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2009.12.055"},{"key":"e_1_2_5_63_1","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E05-01-0055"},{"key":"e_1_2_5_64_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(10)60956-7"},{"key":"e_1_2_5_65_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0176767"},{"key":"e_1_2_5_66_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddp165"},{"key":"e_1_2_5_67_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.90660.2008"},{"key":"e_1_2_5_68_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2005.06.030"},{"key":"e_1_2_5_69_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M606754200"},{"key":"e_1_2_5_70_1","doi-asserted-by":"publisher","DOI":"10.1038\/aps.2011.29"},{"key":"e_1_2_5_71_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceca.2012.12.006"},{"key":"e_1_2_5_72_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1103816108"},{"key":"e_1_2_5_73_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2011.01.011"},{"key":"e_1_2_5_74_1","doi-asserted-by":"publisher","DOI":"10.2174\/1573402111309010003"},{"key":"e_1_2_5_75_1","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/10.12.2219"},{"key":"e_1_2_5_76_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms3980"},{"key":"e_1_2_5_77_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0012305"},{"key":"e_1_2_5_78_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0707120104"},{"key":"e_1_2_5_79_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2007070828"}],"container-title":["The Journal of Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1113%2FJP276796","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/JP276796","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1113\/JP276796","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/JP276796","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,6]],"date-time":"2023-09-06T04:20:52Z","timestamp":1693974052000},"score":1,"resource":{"primary":{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/10.1113\/JP276796"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,10,17]]},"references-count":78,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2019,1]]}},"alternative-id":["10.1113\/JP276796"],"URL":"https:\/\/doi.org\/10.1113\/jp276796","archive":["Portico"],"relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/364679","asserted-by":"object"}]},"ISSN":["0022-3751","1469-7793"],"issn-type":[{"value":"0022-3751","type":"print"},{"value":"1469-7793","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,10,17]]},"assertion":[{"value":"2018-07-07","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-08-31","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-10-17","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}