Tubular basement membrane change occurs pari passu with the development of cyst formation

Our previous studies have shown that 2-amino-4,5-diphenyl thiazole hydrochloride (DPT) administered orally to rats induces a urine concentrating defect (within 1 to 2 days) and progressive, but reversible, cystic change of all collecting tubules (prominent between 4 and 8 weeks). Cystic change was characterized by tubular cell and basement membrane changes consisting of alterations in cellular biosynthetic/secretory organelles, followed by thickening of the basement membrane with marked reduction (approximately 50%) of the de novo synthesis of sulfated proteoglycans, suggesting that altered synthesis of tubular basement membrane plays a role in the development of cystic disease. In this study, following the administration of [14C]-DPT in vivo, a major urinary metabolite (greater than 70%) was isolated by HPLC and characterized by gas chromatographic-mass spectral and NMR analyses as 2-amino-4-hydroxyphenyl-5 phenyl thiazole, designated phenol II. Phenol II was synthesized and administered orally to rats for four days to compare its biological effects with DPT. Phenol II induced a significantly greater impairment of concentrating ability and tubular cystic transformation than DPT. At day 5, in phenol II treated animals, basement membranes lining cysts were thickened several-fold and exhibited extensive loss and disorder of ruthenium red binding sites, indicative of loss of sulfated proteoglycans (heparin sulfate proteoglycan). The basement membrane changes occurred in tandem with the development of cystic transformation and strongly suggests that the basement membrane has a key role in the pathogenesis of PKD. The findings support the hypothesis that PKD may be due to a defect in the synthesis/degradation of one or more basement membrane components (sulfated proteoglycans) resulting in faulty tubular morphogenesis.(ABSTRACT TRUNCATED AT 250 WORDS)