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Altered thick ascending limb function in aging female mice consuming high quantities of fructose‐sweetened water

Fructose (Frc) is metabolized differently from glucose, i.e., with initial metabolism by ketohexokinase (KHK), an enzyme associated with ATP depletion. To test whether a diet enriched in Frc might impair energy‐intensive actions of the renal thick ascending limb (TAL), we evaluated TAL function and protein expression in response to 4‐weeks of 10% Frc in drinking water in young (Y, 3 months) male (M) and female (F) and mid‐aged F (A, 12 months) mice. Frc resulted in, on average, 11% lower kidney weights, regardless of age or sex. In addition, Frc caused a significant reduction in urine concentrating capacity, observed most dramatically in the aged females (F). Urine osmolality was (% of control): 95, 75, and 44 in YMFrc, YFFrc, and AFFrc, respectively. In contrast, Frc increased urine diluting capacity. However, this protective adaptation was attenuated in the AFFrc (urine osmolality % of C): 77 (YMFrc), 76 (YFFrc), 87 (AFFrc). Western blotting revealed 2–5X increased kidney cortex KHK expression in Frc groups, with the increase greatest in YFFrc. Frc resulted in a modest 20–60% increase in band density for the Na‐K‐2Cl cotransporter (NKCC2), the major apical sodium chloride cotransporter of the TAL, but only in Y mice. In the AFFrc it was reduced 30%. In summary, diets enriched in Frc may alter the ability of the TAL to effectively dilute and concentrate urine. Aging subjects may be especially vulnerable. NIH DK082507.