Hereditary error in epidermal growth factor prohormone metabolism in a rat model of autosomal dominant polycystic kidney disease.
Normal Sprague Dawley (SPRD) rats of both sexes secrete an 165 kDa EGF prohormone in urine. Sexually mature Hannover-Sprague Dawley rats (Han:SPRD) heterozygous males and females with autosomal dominant polycystic kidney disease (ADPKD) secrete a prohormone of similar molecular mass in urine. The male, but not the female, also secretes two variant prohormone isoforms with molecular masses close to 200 kDa. Both the 165 and 200 kDa EGF prohormone isoforms are totally absent, in urine, at 11 months of age in male but not in female heterozygous Han:SPRD rats. At this age, the male kidneys exhibit numerous cysts filled with colorless fluids and these fluids contain abundant quantities of a 66 kDa EGF prohormone metabolite. Homozygous Han:SPRD rats which are born with cystic disease secrete only trace amounts of 165 kDa EGF prohormone in their urine while their normal looking littermates secrete the 165 kDa EGF prohormone in abundant quantities. The cyst fluids of homozygous rats contain trace amounts of 165 and 154 kDa EGF prohormone isoforms while the 66 kDa EGF prohormone metabolites present in abundant quantities. The massive amounts of 66 kDa EGF prohormone metabolite in cyst fluids of PKD rats suggests that EGF prohormone and its isoforms undergo aberrant proteolysis in association with cyst pathogenesis both in heterozygous and homozygous kidneys. The specific retention of the 66 kDa EGF prohormone metabolite within the cyst suggests that this molecule may function as a cystogen.
Lakshmanan
J
J
Department of Medicine, Harbor-UCLA Medical Center, UCLA School of Medicine, Torrance 90509.
Eysselein
V
V
D000818:Animals; D004195:Disease Models, Animal; D004815:Epidermal Growth Factor / Q000302:isolation & purification / Q000378:metabolism* / Q000652:urine; D005260:Female; D005799:Genes, Dominant; D006020:Glycopeptides / Q000652:urine; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D015151:Immunoblotting; D007668:Kidney / Q000378:metabolism; D008297:Male; D051379:Mice; D009844:Oligosaccharides / Q000032:analysis; D007690:Polycystic Kidney Diseases / Q000235:genetics* / Q000378:metabolism / Q000652:urine; D011498:Protein Precursors / Q000302:isolation & purification / Q000378:metabolism* / Q000652:urine; D011507:Proteinuria; D051381:Rats; D011922:Rats, Mutant Strains; D017207:Rats, Sprague-Dawley; D012737:Sex Factors
D006020:Glycopeptides; D009844:Oligosaccharides; D011498:Protein Precursors; D004815:Epidermal Growth Factor