Obstructive nephropathy in the neonatal rat is attenuated by epidermal growth factor.
BACKGROUND
Obstructive nephropathy is a primary cause of renal failure in infancy. Chronic unilateral ureteral obstruction (UUO) in the neonatal rat results in reduced renal expression of epidermal growth factor (EGF), renal tubular epithelial (RTE) cell apoptosis and interstitial fibrosis. We wished to determine whether these changes could be prevented by exogenous administration of EGF.


METHODS
Thirty-three Sprague-Dawley rats underwent UUO within the first 48 hours of life, and received daily injections of either EGF (0.1 mg/kg/day) or saline (control) for the following seven days, after which obstructed and intact opposite kidneys were removed for study. These were compared to 11 sham-operated rats that received either no injections, EGF injections, or saline injections. Renal cell proliferation was determined by proliferating cell nuclear antigen, apoptosis was measured by the TUNEL technique, and the distribution of vimentin, clusterin, transforming growth factor-beta 1 (TGF-beta 1), and alpha-smooth muscle actin were determined by immunohistochemistry. Tubular dilation, tubular atrophy, and interstitial collagen deposition were quantitated by histomorphometry.


RESULTS
Compared to controls, EGF treatment increased RTE cell proliferation in the obstructed kidney by 76%, decreased apoptosis by 80%, and reduced vimentin, clusterin and TGF-beta 1 immunostaining (all P < 0.05). EGF treatment reduced tubular dilation by 50%, atrophic tubules by 30%, and interstitial fibrosis by 50% (all P < 0.05). There was no significant effect of EGF on renal alpha smooth muscle actin distribution. There was no effect of saline or EGF injections on kidneys from sham-operated rats for any of the parameters studied.


CONCLUSIONS
We conclude that EGF stimulates RTE cell proliferation and maturation and reduces apoptosis in the neonatal rat kidney subjected to chronic UUO. These effects may contribute to the reduction in tubular dilation, tubular atrophy, and interstitial fibrosis. By preserving renal development, administration of EGF attenuates the renal injury resulting from chronic UUO.
Chevalier
R L
RL
Department of Pediatrics, University of Virginia, School of Medicine, Charlottesville, USA.
Goyal
S
S
Wolstenholme
J T
JT
Thornhill
B A
BA
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002908:Chronic Disease; D051152:Clusterin; D003169:Complement Inactivator Proteins / Q000032:analysis; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D005355:Fibrosis; D006023:Glycoproteins / Q000032:analysis; D007668:Kidney / Q000737:chemistry / Q000166:cytology / Q000254:growth & development*; D007684:Kidney Tubules / Q000254:growth & development / Q000473:pathology; D008026:Ligation; D018832:Molecular Chaperones; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D016212:Transforming Growth Factor beta / Q000032:analysis; D014513:Ureter / Q000601:surgery; D014517:Ureteral Obstruction / Q000188:drug therapy* / Q000473:pathology; D019459:Urothelium / Q000737:chemistry / Q000166:cytology; D014746:Vimentin / Q000032:analysis
D051152:Clusterin; D003169:Complement Inactivator Proteins; D006023:Glycoproteins; D018832:Molecular Chaperones; D018809:Proliferating Cell Nuclear Antigen; D016212:Transforming Growth Factor beta; D014746:Vimentin; D004815:Epidermal Growth Factor