Congenital obstructive nephropathy is the most frequent cause of renal failure in infants and children. The molecular and cellular lesions leading to the congenital obstruction, however, are still largely undetermined. We hypothesize that calcineurin, a serine/threonine phosphatase, is indispensable for the normal development of the excretory system. We have generated a mouse strain with deletion of the CnB gene in a subset of Pax3 positive cells and their derivatives by Cre-mediated LoxP recombination. These mice have deletion of CnB in the excretory system, including the smooth muscle cells in the ureter. The affected mice have hydronephrosis and hydroureter and die from postnatal renal failure. We plan to further determine the nature, the spectrum, as well as the prenatal and postnatal progression of the congenital nephropathy in the mutants. Of particular interests, our previous experiments have demonstrated an indispensable role of calcineurin in the formation of the vascular smooth muscle layer around the major blood vessels. Based on this finding and our preliminary results, we further hypothesize that the disruption of calcineurin function in the ureteral smooth muscle or in the innervating nerves causes a defective peristalsis, leading to the obstructive nephropathy. To test this hypothesis, we will determine whether the mutants have anatomical or functional defects preventing effective peristalsis and will identify the causative cellular lesions. Finally, we will study the ontogeny of the urinary tract smooth muscle cells and the potential neuronal contribution to the congenital nephropathy. The Pax3Cre-CnB mutants we generated have defined genetic modifications and a consistent early onset congenital obstructive nephropathy leading to kidney failure. These mice will serve as a good animal model to study the causes of congenital obstructive nephropathy. Results from the proposed study will also enhance our understanding of the pyeloureteral peristalsis, the ontogeny of ureteral smooth muscle cells, and the role of calcineurin signaling in these processes.
| Li, Song-Zhe; McDill, Bradley W; Kovach, Paul A et al. (2007) Calcineurin-NFATc signaling pathway regulates AQP2 expression in response to calcium signals and osmotic stress. Am J Physiol Cell Physiol 292:C1606-16 |
| McDill, Bradley W; Li, Song-Zhe; Kovach, Paul A et al. (2006) Congenital progressive hydronephrosis (cph) is caused by an S256L mutation in aquaporin-2 that affects its phosphorylation and apical membrane accumulation. Proc Natl Acad Sci U S A 103:6952-7 |
| Chang, Ching-Pin; McDill, Bradley W; Neilson, Joel R et al. (2004) Calcineurin is required in urinary tract mesenchyme for the development of the pyeloureteral peristaltic machinery. J Clin Invest 113:1051-8 |
