Urinary tract obstruction during nephron development causes tubular apoptosis, tubular atrophy, and interstitial fibrosis. Leukocyte recruitment is critical in the development of obstructive nephropathy leading to interstitial inflammation and renal fibrosis. RAGE, the receptor of advanced glycation end products, is implicated in chronic inflammation and has been recently identified as a novel receptor for the β2-integrin Mac-1, cooperating with ICAM-1 and thereby directly mediating leukocyte recruitment in vivo. Here, we studied the role of RAGE and ICAM-1 in a model of unilateral ureteral obstruction in neonatal mice. Interestingly, the number of infiltrating leukocytes was independent of RAGE and ICAM-1 in the ureteral obstructed neonatal kidney. By contrast, galectin-3, a marker for profibrogenic M2 macrophages, was strongly reduced in ureteral obstructed RAGE and RAGE-Icam1 knockout mice. Snail expression and loss of E-cadherin but not NF-κB activation were attenuated in both knockout models. Epithelial cell cycle arrest at G2/M, which mediates kidney fibrosis, and transforming growth factor-β expression were reduced in ureteral obstructed RAGE knockout mice. Thus, RAGE and ICAM-1 promote renal fibrosis in the developing kidney upon ureteral obstruction. Combined RAGE- and ICAM-1-blocking strategies may prove beneficial in neonatal obstructive nephropathy.

Moderate or severe paravalvular regurgitation after transcatheter aortic valve implantation (TAVI) is frequently associated with a loss of high-molecular-weight multimers of von Willebrand factor (VWF) and a reduced VWF collagen-binding capacity. It is unclear whether this phenomenon can also be observed in patients with mild paravalvular regurgitation, and whether there are differences between patients undergoing conventional aortic valve replacement (AVR) or TAVI. We analysed the multimeric structure of VWF and the ratio of VWF collagen-binding capacity to VWF antigen pre- and postoperatively in 12 patients scheduled for AVR and in 31 patients scheduled for TAVI. Echocardiographic examinations were performed pre-, intra- and postoperatively. Nine patients (75%) undergoing AVR and 18 patients (58%) undergoing TAVI showed pathological VWF functionality preoperatively ( = 0.48). Five to 7 days postoperatively, VWF functionality normalised in all patients with AVR, four of them with mild paravalvular regurgitation. VWF functionality was still altered in nine patients after TAVI ( = 0.044 between groups), five of them with and four without mild paravalvular regurgitation ( = 0.1).Altered VWF functionality was observed in nearly one-third of patients after TAVI, but not after AVR. This phenomenon was not related to paravalvular regurgitation, but may indicate differences in the response of the haemostatic system to the prosthetic heart valve design or the valve replacement procedure.