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Large amounts of epidermal growth factor (EGF) are excreted in urine and the majority of this urinary EGF appears to be of renal origin. EGF is synthesized in the kidneys as a membrane-bound 160 kDa precursor, in the thick ascending limb of Henle and in the early part of the distal convoluted tubule. Very little is known about how EGF is released from cell membranes into urine but proteolytic cleavage of the membrane-bound EGF precursor seems likely. The purpose of this study was to examine whether plasma constituents are necessary for urinary excretion of EGF. In the rat isolated kidney perfused at a pressure of 90 mmHg with a modified Krebs-Henseleit buffer containing oncotic agents, the quantity of EGF excreted into the ureteral effluent was 67% of the amount excreted by the rat kidney in vivo. The EGF excreted by the isolated kidney behaved like urinary EGF upon gel filtration. Administration of the proteinase inhibitor aprotinin reduced urinary EGF excretion from the rat isolated perfused kidney by approximately 50%. In conclusion, the rat isolated perfused kidney excreted significant amounts of urinary EGF without having access to plasma, and EGF excretion was reduced by aprotinin. This is further evidence suggesting an intrarenal source of urinary EGF and suggests that the EGF precursor in the rat kidney is processed by enzyme(s) of renal origin.