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      Role of epidermal growth factor receptor in acute and chronic kidney injury

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          Abstract

          Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase. Its activation results in beneficial or detrimental consequences, depending on the particular setting. Earlier studies in the animal model of acute kidney injury showed that EGFR activation promotes renal tubular cell proliferation. Activation of EGFR by its exogenous ligands, like EGF, can enhance recovery of renal function and structure following acute kidney injury. However, recent studies indicated that EGFR activation also contributes to development and progression of renal diseases in animal models of obstructive nephropathy, diabetic nephropathy, hypertensive nephropathy, and glomerulonephritis through mechanisms involved in activation of renal interstitial fibroblasts, induction of tubular atrophy, overproduction of inflammatory factors or/and promotion of glomerular and vascular injury. This review highlights the actions and mechanisms of EGFR in a variety of acute and chronic kidney injuries.

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          Most cited references78

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          Role of tyrosine kinase inhibitors in cancer therapy.

          Cancer chemotherapy has been one of the major medical advances in the last few decades. However, the drugs used for this therapy have a narrow therapeutic index, and often the responses produced are only just palliative as well as unpredictable. In contrast, targeted therapy that has been introduced in recent years is directed against cancer-specific molecules and signaling pathways and thus has more limited nonspecific toxicities. Tyrosine kinases are an especially important target because they play an important role in the modulation of growth factor signaling. This review focuses on small molecule inhibitors of tyrosine kinase. They compete with the ATP binding site of the catalytic domain of several oncogenic tyrosine kinases. They are orally active, small molecules that have a favorable safety profile and can be easily combined with other forms of chemotherapy or radiation therapy. Several tyrosine kinase inhibitors (TKIs) have been found to have effective antitumor activity and have been approved or are in clinical trials. The inhibitors discussed in this manuscript are imatinib mesylate (STI571; Gleevec), gefitinib (Iressa), erlotinib (OSI-1774; Tarceva), lapatinib (GW-572016), canertinib (CI-1033), semaxinib (SU5416), vatalanib (PTK787/ZK222584), sorafenib (BAY 43-9006), sutent (SU11248), and leflunomide (SU101). TKIs are thus an important new class of targeted therapy that interfere with specific cell signaling pathways and thus allow target-specific therapy for selected malignancies. The pharmacological properties and anticancer activities of these inhibitors are discussed in this review. Use of these targeted therapies is not without limitations such as the development of resistance and the lack of tumor response in the general population. The availability of newer inhibitors and improved patient selection will help overcome these problems in the future.
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            Targeted disruption of mouse EGF receptor: effect of genetic background on mutant phenotype.

            Gene targeting was used to create a null allele at the epidermal growth factor receptor locus (Egfr). The phenotype was dependent on genetic background. EGFR deficiency on a CF-1 background resulted in peri-implantation death due to degeneration of the inner cell mass. On a 129/Sv background, homozygous mutants died at mid-gestation due to placental defects; on a CD-1 background, the mutants lived for up to 3 weeks and showed abnormalities in skin, kidney, brain, liver, and gastrointestinal tract. The multiple abnormalities associated with EGFR deficiency indicate that the receptor is involved in a wide range of cellular activities.
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              Dedifferentiation and proliferation of surviving epithelial cells in acute renal failure.

              In contrast to the heart or brain, the kidney can completely recover from an ischemic or toxic insult that results in cell death. During recovery from ischemia/reperfusion injury, surviving tubular epithelial cells dedifferentiate and proliferate, eventually replacing the irreversibly injured tubular epithelial cells and restoring tubular integrity. Repair of the kidney parallels kidney organogenesis in the high rate of DNA synthesis and apoptosis and in patterns of gene expression. As has been shown by proliferating cell nuclear antigen and 5-bromo 2'-deoxyuridine labeling studies and, in unpublished studies, by counting mitotic spindles identified by labeling with antitubulin antibody, the proliferative response is rapid and extensive, involving many of the remaining cells of the proximal tubule. This extensive proliferative capacity is interpreted to reflect the intrinsic ability of the surviving epithelial cell to adapt to the loss of adjacent cells by dedifferentiating and proliferating. Adhesion molecules likely play important roles in the regulation of renal epithelial cell migration, proliferation, and differentiation, as do cytokines and chemokines. Better understanding of all of the characteristics resulting in dedifferentiation and proliferation of the proximal tubule epithelial cell and cell-cell and cell-matrix interactions important for this repair function will lead to novel approaches to therapies designed to facilitate the processes of recovery in humans.
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                Author and article information

                Journal
                0323470
                5428
                Kidney Int
                Kidney Int.
                Kidney international
                0085-2538
                1523-1755
                29 August 2015
                16 January 2013
                May 2013
                29 October 2015
                : 83
                : 5
                : 804-810
                Affiliations
                Department of Medicine, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI 02903. Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
                Author notes
                [* ]Corresponding author: Shougang Zhuang, MD, PhD, Brown University School of Medicine, Rhode Island Hospital - Middle House 301, 593 Eddy Street, Providence, RI 02903, Tel: 401-444-6847, Fax: 401-444-6849, szhuang@ 123456lifespan.org
                Article
                NIHMS427265
                10.1038/ki.2012.435
                4626012
                23325080
                ecb3f3a2-92c4-4866-9689-7f707f5edc13
                History
                Categories
                Article

                Nephrology
                egfr,signaling pathway,acute renal injury,chronic kidney diseases,clinical relevance
                Nephrology
                egfr, signaling pathway, acute renal injury, chronic kidney diseases, clinical relevance

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