title: Impaired phosphorylation of Na(+)-K(+)-2Cl(-) cotransporter by oxidative stress-responsive kinase-1 deficiency manifests hypotension and Bartter-like syndrome.
abstract: Na(+)-K(+)-2Cl(-) cotransporters (NKCCs), including NKCC1 and renal-specific NKCC2, and the Na(+)-Cl(-) 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(-/-) mice were embryonically lethal, OSR1(+/-) 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(-/-) mice had normal BP and hypercalciuria and maintained significant hypokalemia on a low-K(+) diet. KSP-OSR1(-/-) mice exhibited impaired Na(+) reabsorption in the thick ascending loop on a low-Na(+) 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(+) 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(-/-) mice may lead to a Bartter-like syndrome.
authors.affiliation: Division of Nephrology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan.
authors.forename: Shih-Hua
authors.initials: SH
authors.lastname: Lin
authors.forename: I-Shing
authors.initials: IS
authors.lastname: Yu
authors.forename: Si-Tse
authors.initials: ST
authors.lastname: Jiang
authors.forename: Shu-Wha
authors.initials: SW
authors.lastname: Lin
authors.forename: Pauling
authors.initials: P
authors.lastname: Chu
authors.forename: Ann
authors.initials: A
authors.lastname: Chen
authors.forename: Huey-Kang
authors.initials: HK
authors.lastname: Sytwu
authors.forename: Eisei
authors.initials: E
authors.lastname: Sohara
authors.forename: Shinichi
authors.initials: S
authors.lastname: Uchida
authors.forename: Sei
authors.initials: S
authors.lastname: Sasaki
authors.forename: Sung-Sen
authors.initials: SS
authors.lastname: Yang
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism; D001477:Bartter Syndrome / Q000235:genetics / Q000378:metabolism*; D001794:Blood Pressure / Q000502:physiology; D004195:Disease Models, Animal; D007022:Hypotension / Q000235:genetics / Q000378:metabolism*; D007684:Kidney Tubules / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D011188:Potassium / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D011955:Receptors, Drug / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism; D028021:Sodium-Potassium-Chloride Symporters / Q000378:metabolism*; D064466:Solute Carrier Family 12, Member 1; D064506:Solute Carrier Family 12, Member 2; D064486:Solute Carrier Family 12, Member 3; D027981:Symporters / Q000378:metabolism*; D014882:Water-Electrolyte Balance / Q000502:physiology
chemical_list: D011955:Receptors, Drug; C578715:Slc12a1 protein, mouse; C578878:Slc12a2 protein, mouse; C578875:Slc12a3 protein, mouse; D028021:Sodium-Potassium-Chloride Symporters; D064466:Solute Carrier Family 12, Member 1; D064506:Solute Carrier Family 12, Member 2; D064486:Solute Carrier Family 12, Member 3; D027981:Symporters; D012964:Sodium; C486407:Stk39 protein, mouse; C534421:OXSR1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D011188:Potassium