The epidemic of
chronic kidney disease in Nicaragua (
Mesoamerican nephropathy) has been linked with recurrent
dehydration. Here we tested whether recurrent
dehydration may cause renal injury by activation of the
polyol pathway, resulting in the generation of endogenous
fructose in the kidney that might subsequently induce renal injury via metabolism by
fructokinase. Wild-type and
fructokinase-deficient mice were subjected to recurrent heat-induced
dehydration. One group of each genotype was provided water throughout the day and the other group was hydrated at night, after the
dehydration. Both groups received the same total hydration in 24 h. Wild-type mice that received delayed hydration developed renal injury, with elevated serum
creatinine, increased urinary NGAL, proximal tubular injury, and renal
inflammation and
fibrosis. This was associated with activation of the
polyol pathway, with increased renal cortical
sorbitol and
fructose levels.
Fructokinase-knockout mice with delayed hydration were protected from renal injury. Thus, recurrent
dehydration can induce renal injury via a
fructokinase-dependent mechanism, likely from the generation of endogenous
fructose via the
polyol pathway. Access to sufficient water during the
dehydration period can protect mice from developing renal injury. These studies provide a potential mechanism for
Mesoamerican nephropathy.