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Ontogeny of bradykinin B 2 receptors in the rat kidney: Implications for segmental nephron maturation. Kinins modulate renal function, yet their role in the developing kidney is largely unknown. To explore the developmental role of the kallikrein-kinin system, we examined the postnatal ontogeny and intrarenal localization of B 2 receptors in the rat. Northern blot analysis and RT-PCR documented the expression of B 2 receptor mRNA in the kidney and extrarenal tissues of fetal, neonatal and adult animals. The abundance of B 2 receptor mRNA is 10- to 30-fold higher in neonatal than adult tissues in the following order: kidney > heart > aorta > lung > brain. Receptor autoradiography revealed a gradual shift in the localization of bradykinin binding sites from the outer cortex in the newborn to the outer medulla in weanling and maturing rats. The almost complete displacement of [ 125 I]tyr 0 -bradykinin by HOE-140 indicates that the majority of kinin receptors in the developing kidney belong to the B 2 type. Immunolocalization studies using antipeptide antibodies directed against various portions of the receptor revealed that B 2 receptors are first expressed on the luminal aspect of the upper limb of S-shaped bodies and differentiating cortical collecting ducts. In marked contrast, the metanephric mesenchyme, pretubular aggregates and glomeruli display weak or no B 2 receptor immunoreactivity. Following completion of nephrogenesis, B 2 receptor expression shifts to both luminal and basolateral aspects of connecting tubules and collecting ducts. The results demonstrate that bradykinin B 2 receptor gene expression is activated in the developing kidney and cardiovascular system. The spatially restricted expression of B 2 receptors in the differentiating epithelium of the distal nephron, the site of kinin formation, supports the hypothesis that kinins are paracrine modulators of segmental nephron maturation.

The kallikrein-kinin system is involved in the inflammatory process, in blood pressure regulation, and in renal homeostasis. The presence of kallikreins, kininogens, and kinins in renal tissues and fluids is well established; however, the occurrence and distribution of the bradykinin (B2) receptor in the kidney are unknown. Using chemically cross-linked conjugates of bovine serum albumin and the B2 agonist bradykinin or the potent B2 antagonist HOE140, followed by antibodies to the respective ligand and the peroxidase-anti-peroxidase system, we were able to detect the B2 receptor. The receptor has been found in straight portions of the proximal tubules, in distal straight tubules, in connecting tubules, and in collecting ducts of rat kidney. The staining patterns produced by the ligand conjugate-antiligand approach are in agreement with those obtained by conventional autoradiography using [125I]-Tyr0-bradykinin. Immunocytochemical localization of B2 receptor by antipeptide antibodies to the receptor confirmed these findings and demonstrated the presence of B2 receptor in the basal infoldings and luminal membranes of the tubule cells, and in smooth muscle cells of the cortical radial artery and of afferent arterioles. Co-localization of the B2 receptor with kallikrein and kininogens in connecting tubule cell and collecting duct cell layers, respectively, provides a structural basis for the hypothesized physiological functions of the kallikrein-kinin system in the kidney.

Developmental activation and segment-specific co-expression of kininogen and bradykinin (BK) B 2 -receptors during rat nephrogenesis. • 2143