A new rat mutant with chronic conjugated hyperbilirubinemia and renal glomerular lesions.
A new mutant strain of inbred Sprague Dawley rats with autosomal recessive hyperbilirubinuria, were studied by biochemical, histologic, and ultrastructural methods. The plasma bilirubin concentration in the homozygote was significantly higher than that of the heterozygote, and about 80% of the bilirubin was conjugated. Plasma BSP and ICG clearance were both severely delayed in the homozygote. Plasma BSP elimination kinetics suggested that the pathophysiologic defect was not hepatic uptake or storage but rather in secretion into bile. Histopathology of the liver demonstrated brown pigment in the hepatocytes that appeared to be lipofuscin. The electron microscopic features of the hepatic pigment resembled those of the Dubin-Johnson syndrome. Homozygote histopathology also revealed glomerular lesions with mesangial expansion and proliferation in the kidneys. Immunohistologic studies disclosed mesangial granular deposition of IgG, IgA, and to a lesser degree, IgM and C3. These renal changes resembled those of IgA nephropathy. The spontaneous hyperbilirubinuric rat (EHBR) may be a useful animal model for studying constitutive conjugated hyperbilirubinemia, bilirubin metabolism, cholestasis, and glomerulonephropathy subsequent to hepatic dysfunction.
Hosokawa
S
S
Department of Drug Safety Research, Eisai Co., Ltd., Gifu, Japan.
Tagaya
O
O
Mikami
T
T
Nozaki
Y
Y
Kawaguchi
A
A
Yamatsu
K
K
Shamoto
M
M
D000818:Animals; D001663:Bilirubin / Q000652:urine; D002908:Chronic Disease; D004195:Disease Models, Animal; D005260:Female; D005921:Glomerulonephritis / Q000097:blood / Q000235:genetics / Q000473:pathology*; D006933:Hyperbilirubinemia, Hereditary / Q000097:blood / Q000235:genetics / Q000473:pathology*; D007208:Indocyanine Green / Q000493:pharmacokinetics; D008099:Liver / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D008657:Metabolic Clearance Rate; D051381:Rats; D011919:Rats, Inbred Strains; D011922:Rats, Mutant Strains; D013448:Sulfobromophthalein / Q000493:pharmacokinetics
D013448:Sulfobromophthalein; D007208:Indocyanine Green; D001663:Bilirubin