Epidermal growth factor receptor inhibition attenuates early kidney enlargement in experimental diabetes.
BACKGROUND
Renal enlargement is an early feature of both human and experimental diabetes. Although the precise mechanisms underlying its development are incompletely understood, locally active growth factors have been suggested to have a key role. Having previously documented increased expression of the proproliferative and antiapoptotic growth factor, epidermal growth factor (EGF), in early diabetes-related kidney growth, the present study sought to evaluate its pathogenetic role by blocking its action with a specific inhibitor.


METHODS
Sprague-Dawley rats were randomized to receive streptozotocin (diabetic) or buffer (control) and then further randomized to receive either vehicle or the inhibitor of the EGF receptor tyrosine kinase, PKI 166 (100 mg/kg/day) for 2 days and 3 weeks following streptozotocin administration.


RESULTS
Experimental diabetes was associated with an increase in kidney weight and tubular epithelial cell proliferation as identified by increased expression of proliferating cell nuclear antigen (PCNA) and 5-bromo-2'-deoxyuridine (BrdU) incorporation. PKI 166 resulted in a 30% reduction in kidney weight in diabetic rats (P < 0.01) and reduced tubular epithelial cell proliferation (P < 0.01). In addition, EGF receptor inhibition also led to a 40% increase in tubular epithelial cell apoptosis at 3 weeks (P < 0.01). Diabetes-associated glomerular enlargement was similarly attenuated by PKI 166, although glomerular hyperfiltration was unaffected.


CONCLUSIONS
These findings suggest that the EGF-EGF receptor (EGFR) axis has a significant role in the development of early diabetes-related kidney growth. The impact of EGFR inhibition on the later development of renal dysfunction, however, remains to be determined.
Wassef
Lesley
L
Department of Medicine, St. Vincent's Hospital, University of Melbourne, Victoria, Australia.
Kelly
Darren J
DJ
Gilbert
Richard E
RE
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001973:Bromodeoxyuridine / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D004847:Epithelial Cells / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007150:Immunohistochemistry; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D007678:Kidney Glomerulus / Q000473:pathology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D018809:Proliferating Cell Nuclear Antigen; D011743:Pyrimidines; D011758:Pyrroles; C410026:PKI 166; D066246:ErbB Receptors; D001973:Bromodeoxyuridine