ANGIOTENSIN-II RECEPTOR SUBTYPES IN THE HUMAN RENAL-CORTEX AND RENAL-CELL CARCINOMA

Selective antagonists were used to determine the presence of angiotensin II (Ang II) receptor subtypes (AT1 and AT2) in normal human renal cortex and renal cell carcinoma. Normal and tumor tissues were obtained from fresh radical nephrectomy specimens in 7 patients. All patients had a patent renal artery, and the mean preoperative serum creatinine level was 1.1 mg./dl. Tissues were snap frozen and sectioned (14 mum.) for in vitro autoradiography, then incubated in I-125-Ang II (0.3 nM.), with or without unlabeled Ang II or subtype selective antagonists (1 nM. to 1 muM.), rinsed, air dried and apposed to SB-5 X-ray film for 3 to 21 days. In normal renal tissue, low densities of diffuse I-125-Ang II binding sites were observed in cortical areas containing tubules. Higher densities of binding sites occurred over glomeruli and large cortical vessels. Specific binding ranged between 60 and 90% depending on the area as determined by displacement with excess unlabeled Ang II. Specific binding in large cortical vessels was displaced by the two AT2 selective antagonists PD123177 (1 muM.) or CGP 42112A (0.01 muM.), whereas these antagonists were less effective competitors for I-125-Ang II binding in glomeruli. In contrast, the AT1 selective antagonists, DuP 753 and L-158,809 (0.1 and.01 muM., respectively), were potent competitors for glomerular, but not extraglomerular, cortical vessel binding. In the normal cortical tubulointerstitium, both AT1 and AT2 antagonists caused partial displacement of specific binding (55 +/- 12% AT1, 39 +/- 12% AT2). Low density I-125-Ang II binding was present in all tumors. Specific binding averaged 59 +/- 10% as defined by displacement with unlabeled Ang II (1 muM.). As in the normal tubulointerstitial area, each of the selective antagonists produced partial displacement of the specific binding (60 +/- 12% AT1, 31 +/- 8% AT2). In conclusion, AT1 receptors predominate in glomeruli, while AT2 binding sites predominate in large preglomerular vessels of the human renal cortex. In the normal tubulointerstitium and renal cell carcinoma, a 60%/40% mixture of AT1 to AT2 receptors exists. These findings provide a pharmacologic framework for the differential effects of Ang II receptor-mediated function in the human kidney.