Abstract
The microtubule cytoskeleton is composed of α-tubulin and β-tubulin heterodimers, and it serves to regulate the shape, motility, and division of a cell. Post-translational modifications including acetylation are closely associated with the functional aspects of the microtubule, involving in a number of pathological diseases. However, the role of microtubule acetylation in acute kidney injury (AKI) and progression of AKI to chronic kidney disease have yet to be understood. In this study, ischemia/reperfusion (I/R), a major cause of AKI, resulted in deacetylation of the microtubules with a decrease in α-tubulin acetyltransferase 1 (α-TAT1). Paclitaxel (taxol), an agent that stabilizes microtubules by tubulin acetylation, treatment during the recovery phase following I/R injury inhibited tubular cell proliferation, impaired renal functional recovery, and worsened fibrosis. Taxol induced α-tubulin acetylation and post-I/R cell cycle arrest. Taxol aggregated the microtubule in the cytoplasm, resulting in suppression of microtubule dynamics. Our studies have demonstrated for the first time that I/R induced deacetylation of the microtubules, and that inhibition of microtubule dynamics retarded repair of injured tubular epithelial cells leading to an acceleration of fibrosis. This suggests that microtubule dynamics plays an important role in the processes of repair and fibrosis after AKI.
Highlights
Microtubules are one of the primary components of the cytoskeleton, and the microtubule network within the cell plays an essential role in the regulation of cell shape and structure, cell division, and cell motility
We report for the first time that I/R injury causes α-tubulin deacetylation in microtubules, and that inhibition of microtubule dynamics induced by the changes of tubulin acetylation and deacetylation during the recovery phase retards tubule cell regeneration
These findings suggest that the regulation of microtubule dynamics by post-translational modifications could be considered as a treatment modality in acute kidney injury (AKI) and chronic kidney disease (CKD)
Summary
Microtubules are one of the primary components of the cytoskeleton, and the microtubule network within the cell plays an essential role in the regulation of cell shape and structure, cell division, and cell motility. A fibrotic phase characterized by tubule dilatation and atrophy, with expansion of the interstitial space through the accumulation of extracellular matrix, myofibroblasts, and inflammatory cells[8] These sequential changes in response to AKI are strongly correlated with the disorganization, disruption, and aberrant function of the tubule cell cytoskeleton, including the microtubules[9,10]. We demonstrated that AKI resulting from I/R injury induced microtubule deacetylation, inhibited microtubule dynamics, delayed tubule cell recovery and exacerbated fibrosis. These results suggest that regulation of tubulin acetylation and deacetylation, which can regulate microtubule dynamics, could be considered a therapeutic strategy for AKI and CKD treatment
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