It has been shown that collagen XVIII is upregulated shortly after renal ischemia/reperfusion and after renal transplantation, and is involved in glomerulonephritis. In addition, we have shown that monocyte influx upon renal I/R is impaired in mice lacking the BM HSPGs perlecan and collagen XVIII. Renal I/R injury is a process that always occurs after renal transplantation, as well as in acute kidney injury. Although the mechanisms of I/R injury are incompletely understood, the involvement of the innate immune system in I/R injury is well established. Upregulation of inflammatory chemokines, adhesion molecules, complement factors and ECM components upon I/R have been shown. I/R is characterized by an initial phase of inflammation followed by a repair phase in which tubular cells start to proliferate and differentiate to repair tubular damage. These mice also have a better renal function at day 5, demonstrated by lower urea levels in the circulation. Complementing in vitro data show that the GAG polysaccharide side chains of the short collagen XVIII isoform are involved in the binding of L-selectin and MCP-1, facilitating the migration of leukocytes into the inflamed kidney. Together, these data suggest an important role for collagen XV and XVIII in inflammationinduced renal damage after I/R. Tubular damage in I/R model has been shown to be directly related to leukocyte influx. Besides, infiltrated leukocytes, especially monocytes/macrophages contribute to epithelial to mesenchymal transition of the tubular epithelial cells, which upon de-differentiation become ICAM-1/VCAM-1 positive. This tubular expression of adhesion molecules is not involved in leukocyte influx, since this is predominantly orchestrated at the level of the endothelial cells, rather form a retention motif for VLA-4 positive leukocytes and can be used as a measure for tubular activation/de-differentiation. Our compound mutant mice have a better renal function and less tubular damage, most likely due to less inflammatory cell influx into diseased kidney. Therefore, based on our novel and previous findings we consider three different mechanisms underlying the GSK2118436 reduced leukocyte recruitment after I/R in the Col15a12/26Col18a12/2 mice. First, we reported broadened tubular BM in Col18a12/2 mice compared to WT, suggesting that a modified physical structure of BM in our mutant mice could be partially responsible for less leukocyte influx after I/R. Kinnunen et al. showed that although it is not noticeable in normal condition, the tubular BM of collagen XVIII deficient mice shows some structural abnormalities which might result in an altered response after I/R and affect leukocyte influx and the degree of damage. However, that needs further research to be confirmed. Second, Celie et al. previously showed that BM proteoglycans, including collagen XVIII, can bind to L-selectin and facilitate leukocyte migration.