Lack of collagen XVIII/endostatin exacerbates immune-mediated glomerulonephritis.
Collagen XVIII is a component of the highly specialized extracellular matrix associated with basement membranes of epithelia and endothelia. In the normal kidney, collagen XVIII is distributed throughout glomerular and tubular basement membranes, mesangial matrix, and Bowman's capsule. Proteolytic cleavage within its C-terminal domain releases the fragment endostatin, which has antiangiogenic properties. Because damage to the glomerular basement membrane (GBM) accompanies immune-mediated renal injury, we investigated the role of collagen XVIII/endostatin in this disorder. We induced anti-GBM glomerulonephritis in collagen XVIII alpha1-null and wild-type mice and compared the resulting matrix accumulation, inflammation, and capillary rarefaction. Anti-GBM disease upregulated collagen XVIII/endostatin expression within the GBM and Bowman's capsule of wild-type mice. Collagen XVIII/endostatin-deficient mice developed more severe glomerular and tubulointerstitial injury than wild-type mice. Collagen XVIII/endostatin deficiency altered matrix remodeling, enhanced the inflammatory response, and promoted capillary rarefaction and vascular endothelial cell damage, but did not affect endothelial proliferation. Supplementing collagen XVIII-deficient mice with exogenous endostatin did not affect the progression of anti-GBM disease. Taken together, these results suggest that collagen XVIII/endostatin preserves the integrity of the extracellular matrix and capillaries in the kidney, protecting against progressive glomerulonephritis.
Hamano
Yuki
Y
Department of Nephrology, Chiba University Hospital, Chiba, Japan. hamano@faculty.chiba-u.jp
Okude
Takashi
T
Shirai
Ryota
R
Sato
Ikumi
I
Kimura
Ryota
R
Ogawa
Makoto
M
Ueda
Yoshihiko
Y
Yokosuka
Osamu
O
Kalluri
Raghu
R
Ueda
Shiro
S
D000595:Amino Acid Sequence; D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000378:metabolism; D001485:Basement Membrane / Q000378:metabolism; D050476:Bowman Capsule / Q000378:metabolism; D043170:Collagen Type XVIII / Q000172:deficiency / Q000502:physiology*; D003176:Complement C3 / Q000032:analysis; D043169:Endostatins / Q000172:deficiency / Q000502:physiology*; D005260:Female; D005921:Glomerulonephritis / Q000209:etiology*; D007074:Immunoglobulin G / Q000032:analysis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D011817:Rabbits; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis
D043170:Collagen Type XVIII; D003176:Complement C3; D043169:Endostatins; D007074:Immunoglobulin G; D042461:Vascular Endothelial Growth Factor A