A Look at Transactivation of the EGF Receptor by Angiotensin II

A growing number of clinical and experimental studies show that the renin–angiotensin system (RAS) is involved in the progression of CKD.1 In fact, pharmacological inhibitors of the RAS such as angiotensin-converting enzyme inhibitors and angiotensin II (Ang II) type I receptor (AT1R) blockers are the most reliable and effective tools known to attenuate progression of parenchymal changes in CKD.1 However, despite the clinical evidence, understanding how RAS inhibition exerts its renoprotective function at the molecular level remains unclear. Theoretically, Ang II binds to AT1R, a G protein–coupled receptor, predominantly expressed by renal cells.2 Activation of AT1R mediates the majority of Ang II actions through activation of phospholipase C, generation of inositol triphosphate and diacylglycerol, and an increase in intracellular Ca, which in turn stimulates protein kinase C (PKC). In addition, activation of AT1R leads to tyrosine phosphorylation and stimulates mitogen-activated protein (MAP) kinases and growth responses. However, because AT1R lacks intrinsic tyrosine kinase activity, it is not clear how AT1R stimulates extracellular signal kinases 1 and 2 (Erk1 and 2). Several experimental findings suggest that activation of AT1R promotes transactivation of the EGF receptor (EGFR).2–5 This transactivation is likely mediated by metalloproteinase-dependent release of EGFR ligands such as EGF, TGF-a, and heparinbinding EGF (HB-EGF) from their cell membrane–bound precursors and intermediary signaling molecules including intracellular Ca, PKC, and cytosolic tyrosine kinases such as Src kinases.4,5 The contribution of each of these molecular pathways to Ang II–mediated transactivation of EGFR in the kidney with CKD is not known. In the normal adult kidney, high concentrations of EGF are found in urine, and high levels of the EGF precursors are detected in the apical surface of thick ascending limb of Henle and early distal convoluted tubule.5–7 In addition, TGF-a is localized to the distal convoluted tubule and the collecting duct, whereas HB-EGF is localized to the proximal and distal tubules.5,8 EGFR is the prototypical receptor among four members of the receptor tyrosine kinase superfamily and widely expressed in the glomerular mesangium, proximal tubule, collecting duct, and medullary interstitial cells.5 Interestingly, distinct from the apical localization of its ligands, EGFR is localized to the basolateral surface of tubular cells, especially in the proximal tubule. Therefore, different expression sites, as well as different cellular locations, complicate interpretations of interactions between EGFR and its ligands in the kidney under pathologic and experimental conditions. The addition of EGFR ligands to the medium of cultured tubular cells results in activation of EGFR, leading to cell proliferation/hypertrophy, migration, matrix production, and epithelial–mesenchymal transition (EMT).5 As these results suggest, transitory activation of EGFR-regulated genes may be involved in recovery from acute kidney injury.9 In contrast, prolonged activation of EGFR is associated with progressive parenchymal changes of notable pathology in CKD.7,10 The latter is demonstrated in diabetic animals treated with an EGFR tyrosine kinase inhibitor,11 as well as by a histone deacetylase inhibitor,12 in which blockade and attenuated expression of EGFR significantly suppresses diabetesassociated kidney enlargement. Terzi et al.6 also demonstrated this using mice with targeted expression of a dominant negative EGFR (DN-EGFR) transgene in the proximal tubules. After subtotal (;75%) nephrectomy and an ischemia–reperfusion injury, less tubulointerstitial changes develop in these mice than in wild-type controls. Through subsequent independent experiments using JunD gene deficient mice13 and a genomescan analysis,14 Terzi and colleagues proposed that activation of EGFR by paracrine TGF-a plays a pivotal role in development of tubulointerstitial changes after subtotal nephrectomy, at least in FVB/N mice, which are highly susceptible to renoablation. Ang II–dependent transactivation of EGFR has also been shown to play a role in renal lesions after Ang II infusion. Lautrette et al.7 reported that Ang II induced pro–TGF-a and its sheddase, ADAM17, in the apical membranes of distal tubule, activated EGFR and downstream MAP kinases, and generated tubulointerstitial changes in the kidneys of wildtype mice after long-term Ang II infusion. On the other hand, all experimental procedures such as targeted expression of DN-EGFR in the proximal tubule, genomic deletion of the TGF-a gene, and systemic treatment with an ADAM17 inhibitor significantly attenuated development of Ang II–induced renal lesions by inhibition of EGFR phosphorylation. Although this study indicated a potentially detrimental role of cross-talk between Ang II and EGFR in the progression of parenchymal changes in CKD, the paradoxical occurrence in Published online ahead of print. Publication date available at www.jasn.org.