Discordant Spatial Expression of Proliferating Cell Nuclear Antigen (PCNA) and Bradykinin B2 Receptors (B2R) Implicates Kinins in Segmental Nephron Differentiation † 1832

Abstract

We have recently shown that targeted disruption of the B2R gene in mice confers susceptibility to salt-induced congenital renal dysplasia. To examine whether kinins impact nephron epithelial cell proliferation vs. differentiation, we studied the segment-specific expression of B2R and PCNA during nephrogenesis in the rat. PCNA is an essential component of the DNA replication machinery, functioning as the processivity factor for DNA polymerase δ, the enzyme responsible for DNA replication. Actively dividing cells in the S-phase of the cell cycle express high levels of nuclear PCNA. In this study, we determined that kidney, liver, heart and lung B2R and PCNA mRNA/protein expression follow a similar ontogenetic profile, being high in the fetus and newborn only to decline by 2.5 to 6-fold at 2-3 weeks of age(p<0.05). Immunohistochemical studies, however, revealed lack of spatial congruency in B2R and PCNA-expressing cells in the developing kidney. Thus, whereas the cells of metanephrogenic cap and early epithelial precursors in the nephrogenic zone express strong nuclear PCNA immunoreactivity, these cells are essentially devoid of immunoreactive B2R. In contrast, maturing tubules in the inner cortex which stain heavily with B2R are PCNA-negative. The restricted expression of B2R in PCNA-negative nephron segments indicates that kinins promote epithelial differentiation or survival. The data suggest that renal dysplasia in developmentally stressed B2R-knockout mice is due to aberrant epithelial differentiation.