Characterization of inactive renin from human kidney and plasma. Evidence of a renal source of circulating inactive renin.

An inactive form of renin has been isolated from human plasma. It has been suggested that this may represent renin precursor secreted from the kidney. However, early studies failed to isolate inactive renin from human renal tissue. In this investigation, rapid processing of human kidney cortex at temperatures below 4 degrees C in the presence of protease inhibitors followed by cibacron-blue affinity chromatography allowed us to extract a totally inactive form of renal renin. Furthermore, we found that in kidney inactive renin constituted from 10 to as much as 50% of the total renin concentration. Biochemical characterization of the inactive renin from plasma and from kidney indicates that they are structural homologues and, when activated, have enzymatic properties that resemble active renal renin. Renal and plasma inactive renin were found to have the following properties in common: (a) a pH optimum of activation of 3.3; (b) reversible activation by acid dialysis on return to pH 7.4, 37 degrees C; (c) pH optima of enzyme activity of 7.8 with sheep angiotensinogen and 5.5 and 6.7 (biphasic) with human angiotensinogen; (d) Michaelis-Menten constants, Km, of 0.29-0.34 microM with sheep angiotensinogen, and 0.99-1.25 microM with human angiotensinogen; (e) an antibody to human renal renin mean inhibitory titer of 1:30,000 with 1 X 10(-4) Goldblatt units of activated renal or plasma inactive renin; (f) gel filtration profiles consisting of two peaks with apparent molecular weights of 56,000 +/- 1,500 and 49,200 +/- 1,000. Activation of plasma and kidney inactive renin by acid plus renal kallikrein was not accompanied by a change in gel filtration elution patterns. To determine whether inactive renin is released by the kidney, we measured inactive renin in samples obtained simultaneously from both the renal veins and inferior vena cava below the origin of the renal veins. In eight consecutive patients, inactive renin concentration was significantly higher in renal venous blood than in inferior vena caval blood. These data indicate that human kidney contains and secretes significant quantities of inactive renin. Thus, the kidney appears to be a major source of inactive renin in human plasma.