u-0126 and Acute-Kidney-Injury

Topics: Acute Kidney Injury; Animals; Apoptosis; Blood Urea Nitrogen; Butadienes; Cell Proliferation; Cisplatin; Kidney; Lipocalin-2; Lung Neoplasms; MAP Kinase Signaling System; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase Kinases; Neoplasm Proteins; Nitriles; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Tumor Burden

In kidneys, each tubular epithelial cell contains a primary cilium that protrudes from the apical surface. Ciliary dysfunction was recently linked to acute kidney injury (AKI) following renal ischemia-reperfusion. Whether ciliary regulation is a general pathogenic mechanism in AKI remains unclear. Moreover, the ciliary change during AKI and its underlying mechanism are largely unknown. Here we examined the change of primary cilium and its role in tubular cell apoptosis and AKI induced by cisplatin, a chemotherapy agent with notable nephrotoxicity. In cultured human proximal tubular HK-2 epithelial cells, cilia became shorter during cisplatin treatment, followed by apoptosis. Knockdown of Kif3a or Polaris (cilia maintenance proteins) reduced cilia and increased apoptosis during cisplatin treatment. We further subcloned HK-2 cells and found that the clones with shorter cilia were more sensitive to cisplatin-induced apoptosis. Mechanistically, cilia-suppressed cells showed hyperphosphorylation or activation of ERK. Inhibition of ERK by U0126 preserved cilia during cisplatin treatment and protected against apoptosis in HK-2 cells. In C57BL/6 mice, U0126 prevented the loss of cilia from proximal tubules during cisplatin treatment and protected against AKI. U0126 up-regulated Polaris, but not Kif3a, in kidney tissues. It is suggested that ciliary regulation by ERK plays a role in cisplatin-induced tubular apoptosis and AKI.

Topics: Acute Kidney Injury; Animals; Antineoplastic Agents; Apoptosis; Butadienes; Caspases; Cell Line; Cilia; Cisplatin; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; Humans; Kidney Tubules; Male; Mice; Mice, Inbred C57BL; Nitriles