Abundance of the Na-K-2Cl cotransporter NKCC2 is increased by high-fat feeding in Fischer 344 X Brown Norway (F1) rats.
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.
Riazi
Shahla
S
Associate Professor, Dept. of Medicine, Georgetown Univ., 4000 Reservoir Rd, NW, Washington, DC, 20007, USA.
Tiwari
Swasti
S
Sharma
Nikhil
N
Rash
Arjun
A
Ecelbarger
C M
CM
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
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