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This Article Full Text Full Text (PDF) All Versions of this Article: 296/4/F762    most recent 90484.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Riazi, S. Articles by Ecelbarger, C. M. Search for Related Content PubMed PubMed Citation Articles by Riazi, S. Articles by Ecelbarger, C. M.

Abundance of the Na-K-2Cl cotransporter NKCC2 is increased by high-fat feeding in Fischer 344 X Brown Norway (F1) rats

Department of Medicine, Division of Endocrinology and Metabolism, Georgetown University, Washington, DC, 20007

Submitted 13 August 2008 ; accepted in final form 2 February 2009

Insulin resistance is associated with hypertension by mechanisms likely involving the kidney. To determine how the major apical sodium transporter of the thick ascending limb, the bumetanide-sensitive Na-K-2Cl cotransporter (NKCC2) is regulated by high-fat feeding, we treated young male, Fischer 344 X Brown Norway (F344BN) rats for 8 wk with diets containing either normal (NF, 4%) or high (HF, 36%) fat, by weight, primarily as lard. HF-fed rats had impaired glucose tolerance, increased urine excretion of 8-isoprostane (a marker of oxidative stress), increased protein levels for NKCC2 (50–125%) and the renal outer medullary potassium channel (106%), as well as increased natriuretic response to furosemide (20–40%). To test the role of oxidative stress in this response, in study 2, rats were fed the NF or HF diet plus plain drinking water, or water containing N^G-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor (100 mg/l), or tempol, a superoxide dismutase mimetic (1 mmol/l). The combination of tempol with HF nullified the increase in medullary NKCC2, while L-NAME with HF led to the highest expression of medullary NKCC2 (to 498% of NF mean). However, neither of these drugs dramatically affected the elevated natriuretic response to furosemide with HF. Finally, L-NAME led to a marked increase in blood pressure (measured by radiotelemetry), which was significantly enhanced with HF. Mean arterial blood pressure at 7 wk was as follows (mmHg): NF, 100 ± 2; NF plus L-NAME, 122 ± 3; and HF plus L-NAME, 131 ± 2. Overall, HF feeding increased the abundance of NKCC2. Inappropriately high sodium reabsorption in the thick ascending limb via NKCC2 may contribute to hypertension with insulin resistance.

kidney; renal; BSC1; renal outer medullary potassium channel; oxidative stress; insulin resistance; obesity