A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-1 null mutant mice develop renal lesions mimicking obstructive nephropathy

Abstract

BACKGROUND: A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-1 is distinguished from other a disintegrin and metalloproteinase molecules by the presence of thrombospondin type 1 motifs at its C-terminus and anchors to the extracellular matrix. We studied the biological role of ADAMTS-1 in the kidney. METHODS: We developed ADAMTS-1 null mice by replacing exons 2-4, which encode most of the metalloproteinase domain, with the neomycin resistance gene. RESULTS: In normal mice, ADAMTS-1 was detected in the epithelial cells of collecting ducts, and more intensely in the urinary epithelium at the ureteropelvic junction in kidney. We found that targeted disruption of the mouse ADAMTS-1 gene resulted in enlarged renal calices accompanied by bilateral hydronephrosis and papillary atrophy approximately 4 weeks after birth. Electron microscopic examination revealed the fibrotic changes and hypervascularity of capillaries between the urinary epithelial cell layer and smooth muscle cell layer at the ureteropelvic junction. CONCLUSION: ADAMTS-1 appears necessary for normal kidney morphology and function. Moreover, the resemblance of the renal phenotype to human ureteropelvic junction obstruction may provide a clue to the pathogenesis of this common congenital disease.