DEVELOPMENTALLY-REGULATED KALLIKREIN ENZYMATIC-ACTIVITY AND GENE-TRANSCRIPTION RATE IN MATURING RAT KIDNEYS

Kinins are paracrine vasoactive and growth-modulating peptides. Kidney maturation is accompanied by enhanced accumulation of the mRNA encodi ng tissue (renal) kallikrein, a serine protease, and a key component o f the kallikrein-kinin system. To further delineate the developmental regulation of renal kallikrein, we measured tissue kallikrein activity and gene transcription rate during the latter stages of metanephrogen esis. Active tissue kallikrein was measured in renal homogenates by th e amidolytic assay using the fluorogenic substrate D-Val-Leu-Arg-7-ami no-4-methylcoumarin (D-VLR-AMC) in the presence or absence of soybean trypsin inhibitor (SBTI). Kallikrein activity was detectable at very l ow levels in the near-term fetal metanephros. Postnatally, renal kalli krein activity peaked immediately after birth and again at the time of weaning (P < 0.05 vs. other age groups) and remained high in the adul t. Mature female rat kidneys contained 30% more active kallikrein than male kidneys (P < 0.05). The SBTI-sensitive D-VLR-AMC hydrolytic acti vity (due to serine proteases other than tissue kallikrein) accounted for 36-53% of the total renal amidolytic activity. Compared with the 5 -day-old newborn, steady-state renal kallikrein mRNA levels increased threefold by day 12 and sixfold by adulthood. Run-on transcription ana lysis of renal cell nuclei revealed a significant increase in kallikre in gene transcription rate of 80% on day 12 (P < 0.05) and 480% in the adult (P < 0.001). The presence of active kallikrein in the developin g kidney and the upregulation of its synthesis at specific time points during postnatal development implicate intrarenal kinins as potential modulators of renal growth and functional maturation. Furthermore, th e proportional changes in the synthesis of nascent and mature kallikre in RNAs indicate that the renal kallikrein gene is developmentally reg ulated at the transcriptional level.