title: Abundance of the Na-K-2Cl cotransporter NKCC2 is increased by high-fat feeding in Fischer 344 X Brown Norway (F1) rats.
abstract: 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.
authors.affiliation: Associate Professor, Dept. of Medicine, Georgetown Univ., 4000 Reservoir Rd, NW, Washington, DC, 20007, USA.
authors.forename: Shahla
authors.initials: S
authors.lastname: Riazi
authors.forename: Swasti
authors.initials: S
authors.lastname: Tiwari
authors.forename: Nikhil
authors.initials: N
authors.lastname: Sharma
authors.forename: Arjun
authors.initials: A
authors.lastname: Rash
authors.forename: C M
authors.initials: CM
authors.lastname: Ecelbarger
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D015415:Biomarkers / Q000652:urine; D001794:Blood Pressure; D015153:Blotting, Western; D003433:Crosses, Genetic; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004041:Dietary Fats / Q000008:administration & dosage / Q000378:metabolism*; D015237:Dinoprost / Q000031:analogs & derivatives / Q000652:urine; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005665:Furosemide / Q000494:pharmacology; D018149:Glucose Intolerance / Q000378:metabolism* / Q000503:physiopathology; D006973:Hypertension / Q000378:metabolism* / Q000503:physiopathology; D007333:Insulin Resistance; D007679:Kidney Medulla / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009318:Natriuresis; D009569:Nitric Oxide / Q000652:urine; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D018384:Oxidative Stress; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism; D051381:Rats; D011914:Rats, Inbred BN; D011916:Rats, Inbred F344; D049994:Sodium Potassium Chloride Symporter Inhibitors / Q000494:pharmacology; D028021:Sodium-Potassium-Chloride Symporters / Q000378:metabolism*; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D064466:Solute Carrier Family 12, Member 1; D013113:Spin Labels; D013686:Telemetry; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D000975:Antioxidants; D015415:Biomarkers; D003497:Cyclic N-Oxides; D004041:Dietary Fats; D004791:Enzyme Inhibitors; C510692:Kcnj1 protein, rat; D024661:Potassium Channels, Inwardly Rectifying; C578716:Slc12a1 protein, rat; D049994:Sodium Potassium Chloride Symporter Inhibitors; D028021:Sodium-Potassium-Chloride Symporters; D064466:Solute Carrier Family 12, Member 1; D013113:Spin Labels; C075750:8-epi-prostaglandin F2alpha; D009569:Nitric Oxide; D005665:Furosemide; D015237:Dinoprost; D019001:Nitric Oxide Synthase; C499075:Atp1a1 protein, rat; D000254:Sodium-Potassium-Exchanging ATPase; C001803:tempol; D019331:NG-Nitroarginine Methyl Ester