Shortening of primary cilia length is associated with urine concentration in the kidneys

초록

Background: The primary cilium, a microtubule-based cellular organelle present in certain kidney cells, functions as a mechano-sen-sor to monitor fluid flow in addition to various other biological functions. In kidneys, the primary cilia protrude into the tubular lumen and are directly exposed to pro-urine flow and components. However, their effects on urine concentration remain to be defined. Here, we investigated the association between primary cilia and urine concentration. Methods: Mice either had free access to water (normal water intake, NWI) or were not allowed access to water (water deprivation, WD). Some mice received tubastatin, an inhibitor of histone deacetylase 6 (HDAC6), which regulates the acetylation of & alpha;-tubulin, a core protein of microtubules. Results: WD decreased urine output and increased urine osmolality, concomitant with apical plasma membrane localization of aqua-porin 2 (AQP2) in the kidney. After WD, compared with after NWI, the lengths of primary cilia in renal tubular epithelial cells were shortened and HDAC6 activity increased. WD induced deacetylation of & alpha;-tubulin without altering & alpha;-tubulin levels in the kidney. Tubas-tatin prevented the shortening of cilia through increasing HDAC6 activity and consequently increasing acetylated & alpha;-tubulin expression. Furthermore, tubastatin prevented the WD-induced reduction of urine output, urine osmolality increase, and apical plasma mem-brane localization of AQP2. Conclusions: WD shortens primary cilia length through HDAC6 activation and & alpha;-tubulin deacetylation, while HDAC6 inhibition blocks the WD-induced changes in cilia length and urine output. This suggests that cilia length alterations are involved, at least in part, in the regulation of body water balance and urine concentration.

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