ANGIOTENSIN IN RENAL RESPONSE TO URETERAL OBSTRUCTION

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By interfering with renal growth and development , congenital urinary tract obstruction constitutes one of the most important causes of renal failure in infants and children. Obstructive nephropathy is also a significant cause of renal insufficiency in the adult. Unilateral ureteral obstruction (UUO) activates renal programmed cell death (apoptosis) and the renin-angiotensin system. These responses are greater and more prolonged in the neonate than in the adult. Angiotensin II (ANG II) stimulates transforming growth factor-beta 1 and myofibroblast transformation, which may lead to progression of interstitial fibrosis and tubular atrophy in the obstructed kidney. However, acutely following UUO in the neonatal rat, exogenous ANG II increases tubular cell proliferation and decreases apoptosis in the obstructed kidney. We hypothesize that increased renal generation of ANG II is an early protective response to UUO, but that continued production of ANG Il is maladaptive. In the proposed research plan, the renin-angiotensin system will be selectively inhibited (by enalapril, losartan, or PD123319) or stimulated (by ANG II) in neonatal and adult rats with UUO or sham operation. Renal interstitial ANG II will be measured by microdialysis, and the response to single nephron obstruction will be determined by micropuncture. In addition, transgenic mice with 1-4 copies of the angiotensinogen gene will be subjected to UUO or sham operation. Renal tubular cell disruption (determined by focal contact distribution) and apoptosis (determined by flow cytometry and TUNEL) and their modulators (transforming growth factor-beta 1 , clusterin, and bc1-2) will be examined by analysis of mRNA and protein distribution by immunohistochemistry. Renal interstitial myofibroblast transformation and interstitial fibrosis will also be determined. These studies will elucidate the mechanisms by which the renin-angiotensin system regulates the renal cellular responses to UUO, and may lead to new interventions to avert progression of renal insufficiency in patients with obstructive nephropathy.