Cappuccino mutation in an autoimmune-prone strain of mice suggests a role of platelet function in the progression of immune complex crescentic glomerulonephritis.
OBJECTIVE
Crescent formation in the renal glomerulus is a typical manifestation of progressive glomerulopathy associated with fatal renal failure; therefore, its prevention is of clinical importance. Little is known about the pathogenic mechanism for crescent formation. This study was undertaken in an attempt to identify the events that are critical for crescent formation in immune complex crescentic glomerulonephritis (CGN) by analyzing a novel mutant strain of mice.


METHODS
A spontaneous mutant strain of mice was isolated from the autoimmune-prone strain EOD, which stably develops fatal CGN. The mutant phenotypes were assessed histopathologically, hematologically, and immunologically. The mutation was searched for with positional cloning using microsatellite markers.


RESULTS
Compared with wild-type EOD (WT-EOD) mice, mutant EOD (mut-EOD) mice showed marked improvement in CGN in conjunction with an improvement in spontaneous mortality. In WT-EOD mice, an inverse correlation between blood urea nitrogen concentration and blood platelet count and massive accumulation of platelets in the glomerulus were evident, suggesting that an accumulation of platelets in the glomerulus contributes to the progression of CGN. The mutant platelets showed an abnormal aggregation in response to collagen and thrombin, associated with a bleeding tendency in mut-EOD mice. Genetic analysis revealed a deleterious mutation in the cappuccino gene (cno), which encodes a protein that belongs to a complex called the biogenesis of lysosome-related organelle complex 1 and is profoundly involved in platelet function. Morphologic examination revealed a partial defect in dense body formation in the delta-granule of platelets.


CONCLUSIONS
The present findings suggest that platelet functions have a critical role in crescent formation in autoimmune GN.
Yoshida
Minako
M
Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
Saiga
Kan
K
Hato
Takaaki
T
Iwaki
Shoko
S
Niiya
Toshiyuki
T
Arita
Norimasa
N
Komori
Hiroaki
H
Tsubaki
Takahito
T
Furukawa
Hiroshi
H
Terada
Miho
M
Maeyama
Kazutaka
K
Nemoto
Kyuichi
K
Nose
Masato
M
Ono
Masao
M
D000595:Amino Acid Sequence; D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics; D001772:Blood Cell Count; D001792:Blood Platelets / Q000502:physiology*; D001806:Blood Urea Nitrogen; D017931:DNA Primers; D005921:Glomerulonephritis / Q000097:blood / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D015151:Immunoblotting; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D010641:Phenotype; D033921:Vesicular Transport Proteins / Q000235:genetics*
C475462:Bloc1s4 protein, mouse; D017931:DNA Primers; D033921:Vesicular Transport Proteins