NDLI: Impaired phosphorylation of Na+-K+-2Cl− cotransporter by oxidative stress-responsive kinase-1 deficiency manifests hypotension and Bartter-like syndrome

Content Provider	PubMed Central
Author	Lin, Shih-hua Yu, I-shing Jiang, Si-tse Lin, Shu-wha Chu, Pauling Chen, Ann Sytwu, Huey-kang Sohara, Eisei Uchida, Shinichi Sasaki, Sei Yang, Sung-sen
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.
Related Links	http://dx.doi.org/10.1073/pnas.1107452108
Starting Page	17538
File Format	PDF
ISSN	10916490
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	42
Volume Number	108
Language	English
Publisher	National Academy of Sciences
Publisher Date	2011-10-18
Access Restriction	Open
Rights Holder	National Academy of Sciences
Subject Keyword	Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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