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 (TAL), the bumetanide-sensitive Na-K-2Cl cotransporter (NKCC2) is regulated by high-fat feeding, we treated young male, Fisher 344 X Brown Norway (F344BN) rats for 8 weeks 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 (ROMK, 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 NF or HF diet plus plain drinking water, water with L-NAME (L), a nitric oxide synthase (NOS) inhibitor (100 mg/L), or TEMPOL (T), a superoxide dismutase mimetic (1 mmol/L). The combination of T with HF nullified the increase in medullary NKCC2, while L 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 led to a marked increase in BP (measured by radiotelemetry), which was significantly enhanced with HF. Mean arterial BP at 7 weeks were (mm Hg): NF- 100 ± 2, NFL- 122 ± 3, HFL- 131 ± 2. Overall, HF feeding increased the abundance of NKCC2. Inappropriately high sodium reabsorption in the TAL via NKCC2 may contribute to hypertension with insulin resistance.