Pathophysiology of obstructive nephropathy in the newborn.
Congenital obstructive nephropathy is a consequence abnormal urinary tract development resulting in renal growth failure and injury manifested by progressive tubular atrophy and interstitial fibrosis. We have studied the renal cellular and physiological response to unilateral ureteral obstruction (UUO) in the neonatal rodent (guinea pig, rat, and mouse). Whereas in the adult, UUO stimulates renal cellular proliferation, UUO in the neonate reduces nephrogenesis, glomerular maturation, and tubular cellular proliferation. This is accompanied by a proportionately greater compensatory growth of the intact opposite kidney in the neonate. Impaired renal growth and tubular atrophy are likely owing at least in part to stimulation of renal tubular apoptosis. This, in turn, may result from a combination of factors, including loss of epithelial cell polarity, a reduction in the oncoprotein bcl-2 and epidermal growth factor (EGF), and increased expression of the fibrogenic cytokine, transforming growth factor-beta1 (TGF-beta1). Infusion of EGF stimulates cellular proliferation, suppresses apoptosis, and reduces tubular atrophy and interstitial fibrosis. TGF-beta1 is regulated by the renin-angiotensin system, which is markedly activated by UUO in the neonate. The functional consequences of obstructive nephropathy in early development are hyperfiltration by remaining nephrons, followed by progressive decrease in glomerular filtration rate that may only develop in later life. Improved management of congenital urinary tract obstruction will depend on a better understanding of the cellular mechanisms, which may lead to specific treatment using gene therapy or modulators of renal growth and development.
Chevalier
R L
RL
Department of Pediatrics, University of Virginia, Charlottesville 22908, USA.
D000818:Animals; D017209:Apoptosis; D006801:Humans; D007668:Kidney / Q000196:embryology / Q000254:growth & development; D051379:Mice; D051381:Rats; D012084:Renin-Angiotensin System / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000502:physiology; D014517:Ureteral Obstruction / Q000151:congenital* / Q000503:physiopathology
D016212:Transforming Growth Factor beta