Inhibition of microtubule dynamics impedes repair of kidney ischemia/reperfusion injury and increases fibrosis.
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.
Department of Anatomy, Cardiovascular Research Institute, and BK21 Plus, Kyungpook National University School of Medicine, Daegu 700-422, Republic of Korea.
Sang Jun
SJ
Han
Department of Anatomy, Cardiovascular Research Institute, and BK21 Plus, Kyungpook National University School of Medicine, Daegu 700-422, Republic of Korea.
Ji-Hyeon
JH
Kim
Department of Molecular Medicine and MRC, College of Medicine, Keimyung University, Daegu 704-701, Republic of Korea.
Jee In
JI
Kim
Department of Anatomy, Cardiovascular Research Institute, and BK21 Plus, Kyungpook National University School of Medicine, Daegu 700-422, Republic of Korea.
Kwon Moo
KM
Park
D000107:Acetylation; D000818:Animals; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D064447:Checkpoint Kinase 2 / Q000378:metabolism; D003078:Colchicine / Q000494:pharmacology; D018450:Disease Progression; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D007668:Kidney / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism*; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D000067996:RAW 264.7 Cells; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D014404:Tubulin / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects
D014404:Tubulin; D064447:Checkpoint Kinase 2; C578633:Chek2 protein, mouse; D017239:Paclitaxel; D003078:Colchicine