Decreased de novo synthesis of proteoglycans in drug-induced renal cystic disease

Cellular and extracellular (tubular basement membrane, TBM) alterations in the proteoglycans (PGs) of the rat renal tubules in diphenylthiazole-induced cystic disease were investigated. The PGs of normal and cystic kidneys were labeled with [³⁵S]sulfate in an organ-perfusion system. Extracted cellular and TBM PGs were characterized by Sepharose CL-6B chromatography before or after treatment with heparitinase (degrades heparan sulfate) or chondroitinase ABC (degrades chondroitin sulfate). Total radioactivities in cellular, TBM, and medium fractions of cystic kidneys were reduced by factors of 9, 7, and 3, respectively. The PGs obtained from cystic and normal kidneys had similar profiles, namely, two peaks of radioactivity with K(av) values of 0.26 (M(r) = 130,000-150,000) and 0.40 (M(r) = 50,000-55,000). The peaks had variable proportions of radioactivity for cellular and TBM fractions. Besides heparan sulfate, an additional 15-20% of chondroitin sulfate was synthesized in all three fractions obtained from cystic kidneys. The PGs synthesized by cystic kidneys had lower charge-density characteristics as compared to controls by DEAE-Sephacel chromatography. The medium fractions contained mostly glycosaminoglycan chains (K(av) = 0.47, M(r) = 24,000-26,000) of heparan sulfate. Autoradiograms of tissue samples revealed ≃ 50% and ≃ 60% decreases of grain densities over the cellular and TBM compartments, respectively. This decrease in de novo PG synthesis may have some relationship in the pathogenesis of polycystic kidney disease.