4.5 Article

Exocyst Sec10 protects renal tubule cells from injury by EGFR/MAPK activation and effects on endocytosis

Journal

AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
Volume 307, Issue 12, Pages F1334-F1341

Publisher

AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajprenal.00032.2014

Keywords

AKI; EGFR; exocyst; MAPK

Funding

  1. Veterans Affairs (Merit Award)
  2. National Institute of Diabetes and Digestive and Kidney Diseases [DK-069909, DK-070980, K01-DK-087852, R0-3DK-100738]

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Acute kidney injury is common and has a high mortality rate, and no effective treatment exists other than supportive care. Using cell culture models, we previously demonstrated that exocyst Sec10 overexpression reduced damage to renal tubule cells and speeded recovery and that the protective effect was mediated by higher basal levels of mitogen-activated protein kinase (MAPK) signaling. The exocyst, a highly-conserved eight-protein complex, is known for regulating protein trafficking. Here we show that the exocyst biochemically interacts with the epidermal growth factor receptor (EGFR), which is upstream of MAPK, and Sec10-overexpressing cells express greater levels of phosphorylated (active) ERK, the final step in the MAPK pathway, in response to EGF stimulation. EGFR endocytosis, which has been linked to activation of the MAPK pathway, increases in Sec10-overexpressing cells, and gefitinib, a specific EGFR inhibitor, and Dynasore, a dynamin inhibitor, both reduce EGFR endocytosis. In turn, inhibition of the MAPK pathway reduces ligand-mediated EGFR endocytosis, suggesting a potential feedback of elevated ERK activity on EGFR endocytosis. Gefitinib also decreases MAPK signaling in Sec10-overexpressing cells to levels seen in control cells and, demonstrating a causal role for EGFR, reverses the protective effect of Sec10 overexpression following cell injury in vitro. Finally, using an in vivo zebrafish model of acute kidney injury, morpholino-induced knockdown of sec10 increases renal tubule cell susceptibility to injury. Taken together, these results suggest that the exocyst, acting through EGFR, endocytosis, and the MAPK pathway is a candidate therapeutic target for acute kidney injury.

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