Polycystic kidney disease: Primary extracellular matrix abnormality or defective cellular differentiation? Polycystic kidney disease (PKD) is inherited as a dominant or recessive trait or can be provoked by environmental factors. The disease is characterized by the growth of large epithelial-lined cysts derived from the nephrons and collecting ducts of affected kidneys. Cysts are thought to initiate as small dilations in renal tubules, which then expand into fluid-filled cavities of relatively large size. Cyst formation appears to involve increased cell proliferation, reversal of tubular epithelial polarity, and epithelial fluid secretion. In addition, a number of pronounced extracellular matrix changes have been found in the cystic kidneys of several animal models and in human autosomal dominant PKD. These abnormalities include thickened, laminated basement membrane, increased expression of α1 type IV collagen and laminins B1 and B2, and changes in heparan sulfate proteoglycan and fibronectin. Some of these changes can also be seen in vitro, reflecting intrinsic abnormalities, and may be associated with abnormal tubular morphogenesis early in cyst formation as well as later in cyst expansion. We have been investigating gene expression in the C57BL/6J-cpk mouse, which has an autosomal recessive form of PKD, to determine the genetic basis of the abnormal tubule cell growth and morphology manifested during cyst formation. The expression of the proto-oncogenes c-fos, c-myc, and c-Ki-ras is elevated early in the disease process and becomes markedly elevated late in the disease during the most severe stage of cyst development; the elevated c-fos expression in vivo is reflected by hypersensitivity to serum stimulation in vitro, indicating that a basic change has taken place in cystic cells in vivo which persists in cell culture. The preproEGF gene, which normally increases expression during postnatal renal development, is not significantly expressed in cystic kidneys. In contrast, the SGP-2 gene, which is expressed early in nephrogenesis and declines in maturing collecting ducts, shows increasing expression in cystic kidneys. Our results indicate that a number of developmentally regulated genes are abnormally expressed in PKD, suggesting that the disease is caused by defective differentiation of kidney tubules.¹