Role of Serino Protease on the Activation of Inactive Renin in Human Plasma and Its Clinical Significance

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It has been well known that inactive form of renin in human plasma can be converted in vitro into active renin by acid treatment of plasma (acid activation), by cold treatment (cryoactivation) or by enzyme treatment, however the mechanisms of conversion of inactive to active renin and the clinical significances of plasma inactive renin have not been elucidated. In the present study, plasma active and acid activatable inactive renin was measured in healthy subjects and in patients with various diseases, and the relationship among those activation procedures above described was also studied. Acid activation was performed in 24 hr dialysis of plasma to pH 3.3 at 4° followed by additional dialysis to pH 7.2. Plasma renin activity (PRA) was measured by radioimmunoassay. The angiotensin I generated from the incubation of nonacidified plasma with pig renin substrate was expressed as plasma renin concentration (PRC) and that from activated plasma was expressed as total renin concentration (TRC). The inactive renin concentration (IRC) was calculated as TRC minus PRC. With regard to PRA and PRC no significant difference was found between normal and other groups. The values of TRC and IRC were significantly higher in patients with nephrotic syndrome and were lower in those with hyperthyroidism than those in normal subjects. A significant correlation was found between IRC and BUN, and IRC and P. S. P. excretion in 15 minutes. Although PRA and PRC were increased by standing in normal subjects and patients with nephrotic syndrome, no significant changes of TRC and IRC were found in both groups. In order to investigate on the relationship between acid activation and cryoactivation, following studies were performed. Plasma was incubated at -4° for 4 days in cryoactivation and TRC was measured by the same method as the acid activation in this study. We have found that although TRC in acid activation (TRCacid) is higher than TRC in cryoactivation (TRCcryo), there is a significant correlation between the two measurements (r=0.72, p<0.005). The values of TRCcryo for 30 days, however, was approximately equal to those of TRCacid. Trasylol, lima bean trypsin inhibitor (LBTI), diisopropylfluorophosphate (DFP) and phenylmethylsulphonylfluoride (PMSF) were added to the plasma which had been dialyzed to pH 3.3 previously, then those were dialyzed to pH 7.2. DFP and PMSF were added to the pH 7.2 dialysate at the same concentration. Those inhibitors were also added to plasma prior to cryoactivation. Both acid activation and cryoactivation were inhibited by Trasylol, LBTI, DFP and PMSF. Normal human plasma was applied on Blue Sepharose CL-6B and was separated to the passthrough fraction and the 1M-NaCl fraction. The effects of acid activation, cryoactivation, activation by trypsin and kallikrein were compared in the two fractions, respectively. No activation was found in the passthrough fraction, while activation was found in the 1M-NaCl fraction by all four activation procedures. These results show that active and inactive renin in human plasma can be separated by affinity chromatography with Blue Sepharose CL-6B. These data suggest that these activation procedures have an enzymatic basis in common and serine protease plays an important role on activation of plasma inactive renin.
Japan Society of Clinical Chemistryの論文

Role of Serino Protease on the Activation of Inactive Renin in Human Plasma and Its Clinical Significance

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