ACTIVATION OF KININOGEN EXPRESSION DURING DISTAL NEPHRON DIFFERENTIATION

Previous studies have shown that the epithelial precursors of the conn ecting tubule and collecting duct express tissue kallikrein and bradyk inin Bz receptors, respectively, suggesting the presence of a local ki nin-producing/responsive system in the maturing distal nephron. Howeve r, evidence for the existence of kininogen in the developing nephron i s still lacking. This study examined the spatiotemporal relationships between segmental nephron differentiation and the ontogeny of kininoge n and kinins in the rat. Kininogen immunoreactivity is detectable in t he metanephros as early as embryonic day 15. In the nephrogenic zone, the terminal ureteric bud branches are the main kinin-expressing segme nts. Kininogen is also observed in the stromal mesenchyme. In contrast , proximal ureteric bud branches, metanephrogenic mesenchyme, and pret ubular aggregates express little or no kininogen. After completion of nephrogenesis, kininogen distribution assumes its classic ''adult'' pa ttern in the collecting ducts. Peak kininogen mRNA and protein express ion occur perinatally, corresponding to the period of active nephrogen esis in the rat, and declines gradually thereafter. Estimations made b y RT-PCR, Western blotting, and radioimmunoassays indicate that renal kininogen mRNA and protein levels are at least 20-fold higher in newbo rn than adult rats. Likewise, immunoreactive tissue kinin levels are 2 .3-fold higher in newborn than adult kidneys (P < 0.05). In summary, t he present study demonstrates the activation of kininogen gene express ion and kinin production in the developing kidney. The terminal ureter ic bud branches and their epithelial derivatives are the principal kin in-producing segments in the maturing nephron. The results suggest an autocrine/paracrine role for the kallikrein-kinin system in distal nep hron maturation.