Chronic Dehydration Induced Changes in Mouse Supraoptic Nucleus (SON): Contribution to Chronic Kidney Diseases (CKD)?

Abstract

Chronic recurrent dehydration (WAN) can cause CKD, maybe through a fructokinase (KHK) dependent way. VP is a peptide hormone that is synthesized in the hypothalamic SON and paraventricular nucleus (PVN), and is subsequently transported to and stored in posterior pituitary (PP), from where it is released into systemic circulation. VP may mediate some types of CKD through currently unclear mechanisms. Previous studies have demonstrated that acute dehydration (24 hr water deprivation) may activate a local polyol pathway: aldose reductase (AR)‐fructose‐KHK, leading to elevated VP synthesis and secretion, thus worsening CKD. Current studies evaluated the effects of chronic dehydration on the AR‐KHK axis in mouse SON. Mice were subject to heat stress for 30 min at every hour for seven hours during day with limited water access at night only, for five weeks. Mice were sacrificed and SONs and PPs were extracted out and assayed by rtPCR and ELISA for mRNA expression and hormone content, respectively. Chronic dehydration induced significant increase in mRNA expression of the following markers: AR, KHK‐A, KHK‐C, VP, transient receptor potential vanilloid I (TRPV1, the osmo‐sensor), and oxytocin, indicating activation of the AR‐KHK axis and increased VP synthesis /secretion. Further analysis revealed that VP storage in PP was slightly reduced in WT mice by chronic dehydration but was significantly reduced in KHK A/C double knockout mice. KHK‐KO did not significantly affect VP storage in PP of control mice. These results suggest that chronic dehydration may lead to CKD, at least partially, through elevated VP synthesis and secretion driven by activation of the AR‐fructose‐KHK pathway. Future studies will further clarify the underlying mechanisms.Support or Funding InformationDOD PR130106;NIDDK DK048520;AHA12GRNT11940024