title: Specific endothelial heparin-binding EGF-like growth factor deletion ameliorates renal injury induced by chronic angiotensin II infusion.
abstract: Transactivation of EGF receptor (EGFR) by angiotensin II (Ang II) plays important roles in the initiation and progression of chronic kidney diseases. Studies suggest that heparin-binding EGF-like factor (HB-EGF) may be a critical mediator in this process, but its role in vivo has not been investigated. In the current study, we found that in response to Ang II infusion, kidneys from endothelial HB-EGF deletion mice had significantly reduced EGFR activation compared with controls. Meanwhile, deletion of endothelial HB-EGF expression decreased Ang II infusion related renal injury, as demonstrated by 1) less albuminuria; 2) less glomerulosclerosis; 3) preserved endothelial integrity and decreased podocyte injury, as shown by greater glomerular tuft area and WT1-positive cells, and fewer apoptotic cells measured by cleaved caspase 3 staining; 4) reduced inflammation in the perivascular area and interstitium measured by F4/80 and CD3 immunostaining; and 5) reduced renal fibrosis. In conclusion, our results suggest that shedding of HB-EGF from endothelium plays an important role in Ang II-induced renal injury by linking Ang II-AT1R with EGFR transactivation. Inhibition of HB-EGF shedding could be a potential therapeutic strategy for chronic kidney disease.
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Fenghua
authors.initials: F
authors.lastname: Zeng
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Lance A
authors.initials: LA
authors.lastname: Kloepfer
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee; and.
authors.forename: Charlene
authors.initials: C
authors.lastname: Finney
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee; and.
authors.forename: André
authors.initials: A
authors.lastname: Diedrich
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Veterans Affairs, Nashville, Tennessee ray.harris@vanderbilt.edu.
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Harris
mesh_terms: D000419:Albuminuria / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000804:Angiotensin II; D000818:Animals; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D066246:ErbB Receptors / Q000378:metabolism*; D005923:Glomerulosclerosis, Focal Segmental / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D066257:Heparin-binding EGF-like Growth Factor / Q000235:genetics* / Q000378:metabolism; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D051436:Renal Insufficiency, Chronic / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D066257:Heparin-binding EGF-like Growth Factor; D000804:Angiotensin II; D066246:ErbB Receptors
keywords: angiotensin II; chronic kidney disease; heparin-binding epidermal growth factor-like factor