Collagen type XV and XVIII are
proteoglycans found in the basement membrane zones of endothelial and epithelial cells, and known for their cryptic anti-angiogenic domains named
restin and
endostatin, respectively. Mutations or deletions of these
collagens are associated with eye, muscle and microvessel phenotypes. We now describe a novel role for these
collagens, namely a supportive role in leukocyte recruitment. We subjected mice deficient in
collagen XV or
collagen XVIII, and their compound mutant, as well as the wild-type control mice to bilateral renal
ischemia/reperfusion, and evaluated renal function, tubular injury, and neutrophil and macrophage influx at different time points after
ischemia/reperfusion. Five days after
ischemia/reperfusion, the
collagen XV,
collagen XVIII and the compound mutant mice showed diminished serum
urea levels compared to wild-type mice (all p<0.05). Histology showed reduced tubular damage, and decreased inflammatory cell influx in all mutant mice, which were more pronounced in the compound mutant despite increased expression of MCP-1 and TNF-α in double mutant mice compared to wildtype mice. Both type XV and
type XVIII collagen bear
glycosaminoglycan side chains and an in vitro approach with recombinant
collagen XVIII fragments with variable glycanation indicated a role for these side chains in leukocyte migration. Thus, basement membrane zone
collagen/
proteoglycan hybrids facilitate leukocyte influx and tubular damage after renal
ischemia/reperfusion and might be potential intervention targets for the reduction of
inflammation in this condition.