Mechanisms of EGFR Activation and Signaling in Kidney Disease

Vanderbilt University Medical Center, Nashville TN

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Abstract

? DESCRIPTION (provided by applicant): The Epidermal Growth Factor Receptor (EGFR; ErbB1) is widely expressed in the kidney in both glomeruli and tubules. Our previous studies have elucidated a dichotomous role for EGFR activation in kidney injury, with regulated activation following acute kidney injury (AKI) serving as an important and necessary step for recovery but with persistent and dysregulated activation mediating progressive glomerular and tubulointerstitial injury in progressive kidney diseases. Genetic or pharmacologic inhibition of EGFR activation can be an effective therapeutic intervention in experimental models of chronic kidney disease. Translating this insight into human disease is complicated by known skin side effects of current EGFR tyrosine kinase inhibitors or receptor antibodies. However, given its potential biological relevance, mechanisms to inactivate the EGFR pathway still hold great promise as a therapeutic option, especially if more selective targeting of downstream signaling pathways can be achieved. The mechanisms of EGFR activation in response to acute or chronic kidney injury remain incompletely understood and may involve both ligand- dependent and ligand-independent mechanisms. Furthermore, although recent studies have identified novel mechanisms for augmenting or inhibiting EGFR membrane localization and activation, whether these mechanisms play a role in kidney injury is unknown. The mechanisms and signaling pathways underlying progressive glomerulopathy and tubulointerstitial fibrosis secondary to aberrant EGFR signaling in chronic disease have not be elucidated, nor is is It known whether the same mechanisms mediate EGFR-dependent recovery from AKI. Thus, our overall goal is to determine the molecular mechanisms underlying EGFR-mediated effects in both acute and chronic kidney disease in order to identify more selective therapeutic targets. To accomplish this goal, we propose three specific aims:1) Determine the mechanisms by which EGFR is activated in response to acute or chronic kidney injury. In this aim we will examine both ligand-dependent and ligand- independent mechanisms of EGFR activation in AKI and CKD; 2) determine the mechanisms by which EGFR mediates kidney fibrosis in chronic kidney injury. We will determine the role of EGFR in TGF-ß production and myofibroblast induction and the role of aberrant YAP/TAZ signaling in EGFR- mediated renal fibrosis; and 3) Determine the mechanisms by which EGFR activation inhibits autophagy. We wil determine the mechanism(s) by which EGFR activation inhibits AMP kinase activity and inhibits autophagy in diabetic nephropathy.