Kinins are postulated to play a role in kidney maturation through modulation of renal growth and function. Studies in the rat have shown that the developing kidney expresses all the components of the kallikrein-kinin system, and that bradykinin B2 receptors are highly expressed in the maturing distal nephron segments. Preliminary investigations of kidney development in rats subjected to B2 blockade or mice with a targeted disruption of the B2 gene have revealed abnormal collecting duct development only if B2 blockade/ablation is combined with an intrauterine stress, such as chronic salt loading. Accordingly, the hypothesis to be tested in this project is that the B2-deficient mouse is a genetically susceptible host, in that loss of B2 function predisposes the developing animal to aberrant distal nephrogenesis in a stressed fetal-maternal unit.
The Specific Aims are: 1) to demonstrate that the differentiating distal nephron expresses a local kinin generating (responsive) system. The segmental and cellular localization of bradykinin-producing and B2 receptor-expressing cells during murine nephrogenesis will be detemmined by immunohistochemistry and in situ hybridization histochemistry; 2) to demonstrate that developmentally stressed mice with B2 geno ablation manifest aberrant distal nephrogenesis and a progressive dysplastic nephropathy. B2-defident mice will be subjected to intrauterine salt loading and examined during fetal and postnatal development for evidence of delayed segmental nephron growth/differentiation, aberrant spatial and temporal expression of epidemal growth factor/receptor, segment-specific abnommalities in cell survival/division, and persistent nephropathy and hypertension; and 3) to test the hypothesis that disordered segmental nephron maturation is etiologically linked to the development of salt-sensitive hypertension. The results of the proposed research should elucidate the role of the kallikrein-kinin system in the normal developmental program of segmental nephron maturation. In addition, the results may provide important insights into the role of gene/environment interactions in the pathogenesis of congenital disorders of organogenesis/differentiation.
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