{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T19:04:58Z","timestamp":1790017498531,"version":"4.0.1"},"reference-count":36,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2003,12,1]],"date-time":"2003-12-01T00:00:00Z","timestamp":1070236800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2003,12]]},"abstract":"<jats:p>The apical Na<jats:sup>+<\/jats:sup>\u2010H<jats:sup>+<\/jats:sup> exchanger NHE3 plays an important role in fluid reabsorption in the proximal tubule. However, whether its deletion alters the salt and water transport in the distal nephron remains unknown. To answer these questions, wild\u2010type (<jats:italic>Nhe3<jats:sup>+\/+<\/jats:sup><\/jats:italic>) and NHE3 null mice (<jats:italic>Nhe3<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic>) were placed in metabolic cages and their water balance and urine osmolality were examined. <jats:italic>Nhe3<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> mice demonstrated a significant polydipsia (<jats:styled-content><jats:italic>P<\/jats:italic> &lt; 0.03<\/jats:styled-content>) and polyuria (<jats:styled-content><jats:italic>P<\/jats:italic> &lt; 0.04<\/jats:styled-content>), with a lower urine osmolality (<jats:styled-content><jats:italic>P<\/jats:italic> &lt; 0.003<\/jats:styled-content>) as compared to <jats:italic>Nhe3<jats:sup>+\/+<\/jats:sup><\/jats:italic> mice. Northern hybridization and immunoblotting studies indicated that the mRNA expression and protein abundance of the collecting duct (CD) water channel AQP2 decreased by 52 % (<jats:styled-content><jats:italic>P<\/jats:italic> &lt; 0.0003<\/jats:styled-content>) and 73 % (<jats:styled-content><jats:italic>P<\/jats:italic> &lt; 0.003<\/jats:styled-content>) in the cortex, and by 53 % and 54 % (<jats:styled-content><jats:italic>P<\/jats:italic> &lt; 0.002<\/jats:styled-content>) in the inner medulla (IM) of <jats:italic>Nhe3<jats:sup>\u2212\/\u2212<\/jats:sup> vs<\/jats:italic>. <jats:italic>Nhe3<\/jats:italic><jats:sup>+\/+<\/jats:sup> mice. The expression of AQP2 in the outer medulla (OM) remained unchanged. Further, the mRNA expression and protein abundance of the medullary thick ascending limb (mTAL) apical Na<jats:sup>+<\/jats:sup>\u2010K<jats:sup>+<\/jats:sup>\u20102Cl<jats:sup>\u2212<\/jats:sup> cotransporter (NKCC2) decreased by 52 % (<jats:styled-content><jats:italic>P<\/jats:italic> &lt; 0.02<\/jats:styled-content>) and 44 % (<jats:styled-content><jats:italic>P<\/jats:italic> &lt; 0.01<\/jats:styled-content>), respectively, in the OM of <jats:italic>Nhe3<jats:sup>\u2212\/\u2212<\/jats:sup> vs<\/jats:italic>. <jats:italic>Nhe3<\/jats:italic><jats:sup>+\/+<\/jats:sup> mice. The circulating plasma levels of vasopressin as well as the mRNA expression of vasopressin prohormone were significantly increased in <jats:italic>Nhe3<jats:sup>\u2212\/\u2212<\/jats:sup> vs<\/jats:italic>. <jats:italic>Nhe3<\/jats:italic><jats:sup>+\/+<\/jats:sup> mice (<jats:styled-content><jats:italic>P<\/jats:italic> &lt; 0.05<\/jats:styled-content>). Studies in mice treated with acetazolamide indicated that increased bicarbonate and fluid delivery to distal nephron did not alter the expression of NKCC2 in mTAL and decreased AQP2 protein only in OM but not in the cortex or IM. In conclusion, mice lacking the apical NHE3 have impairment in their water balance and urine osmolality, which correlates with the downregulation of AQP2 expression. These defects occur despite increased circulating levels of vasopressin. We propose that an ADH\u2010independent mechanism is responsible for the downregulation of AQP2 and the resulting polyuria in NHE3 null mice.<\/jats:p>","DOI":"10.1113\/jphysiol.2003.053363","type":"journal-article","created":{"date-parts":[[2003,9,23]],"date-time":"2003-09-23T01:31:49Z","timestamp":1064280709000},"page":"511-522","source":"Crossref","is-referenced-by-count":21,"title":["Downregulation of renal AQP2 water channel and NKCC2 in mice lacking the apical Na<sup>+<\/sup>\u2010H<sup>+<\/sup> exchanger NHE3"],"prefix":"10.1113","volume":"553","author":[{"given":"Hassane","family":"Amlal","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clara","family":"Ledoussal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sulaiman","family":"Sheriff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary E.","family":"Shull","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manoocher","family":"Soleimani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2003,12]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"crossref","first-page":"F513","DOI":"10.1152\/ajprenal.2001.280.3.F513","article-title":"Fasting downregulates renal. water channel AQP\u20102 and causes polyuria","volume":"280","author":"Amlal H","year":"2001","journal-title":"Am J Physiol Renal Physiol"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.2000.279.4.F655"},{"key":"e_1_2_5_4_1","doi-asserted-by":"crossref","first-page":"C455","DOI":"10.1152\/ajpcell.1996.271.2.C455","article-title":"Na+ \u2010K+ (NH4\n                  +)\u20102Cl\u2212 cotransport in medullary thick ascending limb: control by PKA, PKC, and 20\u2010HETE","volume":"271","author":"Amlal H","year":"1996","journal-title":"Am J Physiol"},{"key":"e_1_2_5_5_1","doi-asserted-by":"crossref","first-page":"C1047","DOI":"10.1152\/ajpcell.1998.274.4.C1047","article-title":"Ang II controls Na+ \u2010K+\u2010(NH4\n                  +)\u20102Cl\u2212 cotransport via 20\u2010HETE and PKC in medullary thick ascending limb","volume":"274","author":"Amlal H","year":"1998","journal-title":"Am J Physiol"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI686"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1523-1755.2003.00110.x"},{"key":"e_1_2_5_8_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI107848"},{"key":"e_1_2_5_9_1","doi-asserted-by":"crossref","first-page":"1204","DOI":"10.1152\/ajplegacy.1976.231.4.1204","article-title":"Impaired urinary concentrating ability and cyclic AMP in K+\u2010depleted rat kidney","volume":"231","author":"Beck N","year":"1976","journal-title":"Am J Physiol"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7793.2001.0359k.x"},{"key":"e_1_2_5_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF01464780"},{"key":"e_1_2_5_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/ki.1976.20"},{"key":"e_1_2_5_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/0003-2697(87)90021-2"},{"key":"e_1_2_5_14_1","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1073\/pnas.81.7.1991","article-title":"Genomic sequencing","volume":"81","author":"Church GM","year":"1984","journal-title":"Proc Natl Acad Sci U S A"},{"key":"e_1_2_5_15_1","doi-asserted-by":"publisher","DOI":"10.1097\/00041552-199509000-00003"},{"key":"e_1_2_5_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/361549a0"},{"key":"e_1_2_5_17_1","first-page":"F745","article-title":"Control of NaCl transport in the thick ascending limb","volume":"253","author":"Hebert SC","year":"1984","journal-title":"Am J Physiol"},{"key":"e_1_2_5_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF01868440"},{"key":"e_1_2_5_19_1","first-page":"F412","article-title":"NaCl transport in mouse medullary thick ascending limbs. 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