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Superoxide enhances Na-K-2Cl cotransporter activity in the thick ascending limb

Division of Hypertension and Vascular Research, Henry Ford Hospital, Detroit, Michigan

Submitted 16 September 2004 ; accepted in final form 11 January 2005

Superoxide (O₂^–) enhances Na reabsorption by the thick ascending limb (THAL). Na absorption in this segment involves the Na-K-2Cl cotransporter, K channel, and Na-K-ATPase. We hypothesized that O₂^– stimulates NaCl absorption primarily by enhancing Na-K-2Cl cotransport. First, we measured steady-state intracellular Na (Na_i) and chloride (Cl_i). Xanthine oxidase (XO; 0.75 mU/ml) and hypoxanthine (HX; 0.125 mM) were added to the bath to increase O₂^–. During the control period, Na_i was 12.2 ± 1.9 mM. After treatment with O₂^–, it rose to 20.9 ± 3.3 mM, a 71% increase (P < 0.01). Cl_i also increased (P < 0.01). Neither XO nor HX alone had a significant effect on Na_i or Cl_i. Next, we tested cotransport activity by measuring the initial rate of increase in Na_i caused by changing luminal Na-Cl-K from 50/0/0 to 140/134/4 mM. During the control period, the initial rate of increase was 0.13 ± 0.02 arbitrary units (AU)/min. After treatment with O₂^–, it was 0.22 ± 0.04 AU/min (P < 0.025), a 69% increase. Neither XO nor HX alone had a significant effect. Furosemide completely blocked the increase in intracellular Na in the control and O₂^– treatment periods. Next, we studied K channel activity by measuring the depolarization caused by increasing luminal K from 1 to 25 mM using a voltage-sensitive dye. During the control period, maximum depolarization was 7.31 ± 0.77 AU. After O₂^– treatment, it was 6.18 ± 0.90 AU (P < 0.05), a 15% decrease. Finally, we assessed the effects of O₂^– on Na-K-ATPase activity in THAL suspensions by measuring ATP hydrolysis. V_max and K_1/2 for Na were not affected by O₂^–. We concluded that O₂^– stimulates THAL NaCl absorption primarily by enhancing Na entry via Na-K-2Cl cotransport.

reactive oxygen species; transport; Na-K-ATPase; K channels; NKCC2

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