Obstructive nephropathy is a major cause of renal insufficiency at all ages. However, the mechanisms of renal injury due to urinary tract obstruction and of compensatory adaptation by unobstructed nephrons remain poorly understood. Since a critical role of the intrarenal renin-angiotensin system (RAS) in regulation of renal function is now established, the overall objective of the proposed study is to elucidate the role of individual components of the RAS In the renal response to unilateral ureteral obstruction (UUO). To evaluate the renal functional consequences of UUO in early development, maturational effects will also be considered. The effects of renal denervation, the response to relief of UUO, and compensatory adaptation by the intact contralateral kidney, will be investigated with respect of physiologic and molecular changes int he intrarenal RAS. Neonatal and adult rats will be subjected to UUO or sham operation, and renal blood flow, glomerular filtration rate, and renal renin content will be measured. Renin and angiotensinogen messenger RNA (mRNA) will be measured by complementary DNA (cDNA) probe, and renin release by individual renal cells will be determined by the reverse hemolytic plaque assay. since ureteral obstruction results in considerable functional nephron heterogeneity, the intrarenal distribution of renin and angiotensinogen mRNA will be studied by in situ cDNA hybridization, while distribution of stored renin will be determined by immunohistochemistry. To evaluate the effects of individual tubular obstruction on the associated juxtaglomerular apparatus, tubules of Munich-Wistar rats will be blocked by micropuncture. Juxtaglomerular renin and angiotensinogen mRNA and renin immunostaining will be measured as above in obstructed and nonobstructed nephrons. Renin release will be determined in glomeruli isolated by microdissection. To determine the endogenous activity of the RAS, the effects of angiotensin converting enzyme inhibition and renin inhibition and renin inhibition on function of both kidneys will be measured in neonatal and adult guinea pigs with chronic partial UUO. Counteraction of the RAS by endogenous prostaglandins, and atria natriuretic peptide will also be examined. The results of the proposed experiments should enhance our knowledge of tubuloglomerular feedback mechanisms and physiologic control of the RAS as well as benefiting the care of infants, children, and adults with urinary tract obstruction.
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