Molecular basis of autosomal dominant polycystic kidney disease.

Recent studies have identified the genes mutated in the two major forms of autosomal dominant polycystic kidney disease, PKD1 and PKD2. The PKD1 gene product is likely to be a very large membrane-associated glycoprotein that functions as a receptor for cell-cell or cell-matrix interactions. PKD2 has significant homology to the family of voltage-activated calcium channels. Both proteins are expressed in the developing kidney and appear to have an overlapping pattern of expression. Several studies suggest that the gene products are interacting partners of a signaling pathway. Studies of human tissue suggest a two-hit genetic mechanism is responsible for both forms of the disease. Consistent with this hypothesis, murine models engineered with loss-of-function mutations of Pkd1 or Pkd2 develop cystic disease in the homozygous state. In these animals, renal development proceeds normally through day 15, at approximately which time renal cysts begin to form. The studies suggest an essential role for the PKD proteins in regulating later stages of tubular maturation. The animal models will be useful resources for defining the pathogenesis of autosomal dominant polycystic kidney disease and testing various therapeutic interventions. The two-hit model has potentially important clinical implications.