OP.5A.08] HCARG/COMMD5 IMPROVES KIDNEY REPAIR BY REGULATING EGF RECEPTOR TRAFFICKING

Abstract

Objective: Epidermal Growth Factor Receptor (EGFR) is crucially involved in nephrogenesis. Although, constitutive EGFR signaling is needed for normal kidney development and can enhance recovery of renal function and structure following acute kidney injury, its overexpression may leads to excess renal tissue fibrosis and functional deterioration in diabetic and hypertensive nephropathy. Consequently, targeting EGFR in renal diseases is complex. Our group has identified HCaRG (Hypertension-related, Calcium-Regulated Gene), currently named COMMD5, whose overexpression in an in vivo model of renal carcinoma inhibited tumor growth and angiogenesis by inhibiting EGFR activation and downstream signaling. Overexpression of COMMD5 in renal proximal tubules of transgenic mice increased mice survival and recovery of renal tissue integrity and function after acute kidney injury. Our goal is to demonstrate that COMMD5 accelerated kidney repair by controlling EGFR activity, endocytosis and trafficking. Design and method: COMMD5 was silenced by siRNA and EGFR expression and activation were evaluated in renal cell lines. Intracellular localization of COMMD5, EGFR and endosome associated protein, such as Rab, were analyzed by confocal microscopy and live cell imaging. Co-immunoprecipitations were used to investigate interactions between COMMD5 and proteins known to be involved in vesicle trafficking. Results: We demonstrated that COMMD5 is an adaptor protein forming a bridge between endosomes and cytoskeleton by binding Rab protein and microtubules/actin. This tethering is essential because silencing of COMMD5 delayed the intracellular transport dynamic and consequently cargo protein such as EGFR. Defect in intracellular trafficking led to loss of cell polarity and oriented migration which are crucial for tissue repair. Conclusions: Our results demonstrated that COMMD5 plays a crucial role in controlling EGFR signaling/trafficking and suggest that COMMD5 could be used as a novel target for EGFR-targeted therapy in kidney diseases.