{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T20:54:14Z","timestamp":1793134454403,"version":"4.5.0"},"reference-count":37,"publisher":"National Academy of Sciences","issue":"42","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2011,10,18]]},"abstract":"<jats:p>\n                    Na\n                    <jats:sup>+<\/jats:sup>\n                    -K\n                    <jats:sup>+<\/jats:sup>\n                    -2Cl\n                    <jats:sup>\u2212<\/jats:sup>\n                    cotransporters (NKCCs), including NKCC1 and renal-specific NKCC2, and the Na\n                    <jats:sup>+<\/jats:sup>\n                    -Cl\n                    <jats:sup>\u2212<\/jats:sup>\n                    cotransporter (NCC) play pivotal roles in the regulation of blood pressure (BP) and renal NaCl reabsorption. Oxidative stress-responsive kinase-1 (OSR1) is a known upstream regulator of N(K)CCs. We generated and analyzed global and kidney tubule-specific (KSP) OSR1 KO mice to elucidate the physiological role of OSR1 in vivo, particularly on BP and kidney function. Although global OSR1\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice were embryonically lethal, OSR1\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    mice had low BP associated with reduced phosphorylated (p) STE20 (sterile 20)\/SPS1-related proline\/alanine-rich kinase (SPAK) and p-NKCC1 abundance in aortic tissue and attenuated p-NKCC2 abundance with increased total and p-NCC expression in the kidney. KSP-OSR1\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice had normal BP and hypercalciuria and maintained significant hypokalemia on a low-K\n                    <jats:sup>+<\/jats:sup>\n                    diet. KSP-OSR1\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice exhibited impaired Na\n                    <jats:sup>+<\/jats:sup>\n                    reabsorption in the thick ascending loop on a low-Na\n                    <jats:sup>+<\/jats:sup>\n                    diet accompanied by remarkably decreased expression of p-NKCC2 and a blunted response to furosemide, an NKCC2 inhibitor. The expression of total SPAK and p-SPAK was significantly increased in parallel to that of total NCC and p-NCC despite unchanged total NKCC2 expression. These results suggest that, globally, OSR1 is involved in the regulation of BP and renal tubular Na\n                    <jats:sup>+<\/jats:sup>\n                    reabsorption mainly via the activation of NKCC1 and NKCC2. In the kidneys, NKCC2 but not NCC is the main target of OSR1 and the reduced p-NKCC2 in KSP-OSR1\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice may lead to a Bartter-like syndrome.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1107452108","type":"journal-article","created":{"date-parts":[[2011,10,5]],"date-time":"2011-10-05T00:23:00Z","timestamp":1317774180000},"page":"17538-17543","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":132,"title":["Impaired phosphorylation of Na\n                    <sup>+<\/sup>\n                    -K\n                    <sup>+<\/sup>\n                    -2Cl\n                    <sup>\u2212<\/sup>\n                    cotransporter by oxidative stress-responsive kinase-1 deficiency manifests hypotension and Bartter-like syndrome"],"prefix":"10.1073","volume":"108","author":[{"given":"Shih-Hua","family":"Lin","sequence":"first","affiliation":[{"name":"Division of Nephrology, Department of Medicine, Tri-Service General Hospital,"},{"name":"Graduate Institute of Medical Sciences, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I-Shing","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei 100, Taiwan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Si-Tse","family":"Jiang","sequence":"additional","affiliation":[{"name":"National Laboratory Animal Centre, National Applied Research Laboratories, Taipei 115, Taiwan; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu-Wha","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei 100, Taiwan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pauling","family":"Chu","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, Tri-Service General Hospital,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann","family":"Chen","sequence":"additional","affiliation":[{"name":"Graduate Institute of Medical Sciences, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huey-Kang","family":"Sytwu","sequence":"additional","affiliation":[{"name":"Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Taipei 114, Taiwan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eisei","family":"Sohara","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinichi","family":"Uchida","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sei","family":"Sasaki","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sung-Sen","family":"Yang","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, Tri-Service General Hospital,"},{"name":"Graduate Institute of Medical Sciences, and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2011,10,4]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00083.2002"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.01402.2006"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00309.2005"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.90392.2008"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00011.2004"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.1999.276.3.C511"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1097\/MNH.0b013e3283360a46"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1062844"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng0696-183"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng0196-24"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1007\/s100380050121"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1203784"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M208108200"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M510042200"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20051180"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1097\/MNH.0b013e32830dd580"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2007.03.009"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddp344"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2009121295"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1053\/j.ajkd.2007.02.267"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20071324"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1002\/emmm.200900058"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00325.2007"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI118844"},{"key":"e_1_3_3_25_2","first-page":"49","article-title":"Roles of the kidneys and fluid volumes in arterial pressure regulation and hypertension","volume":"32","author":"Guyton AC","year":"1989","unstructured":"AC Guyton, Roles of the kidneys and fluid volumes in arterial pressure regulation and hypertension. 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