Renal Urokinase-Type Plasminogen Activator (uPA) Receptor but not uPA Deficiency Strongly Attenuates Ischemia Reperfusion Injury and Acute Kidney Allograft Rejection

Abstract

Central mechanisms leading to ischemia induced allograft rejection are apoptosis and inflammation, processes highly regulated by the urokinase-type plasminogen activator (uPA) and its specific receptor (uPAR). Recently, up-regulation of uPA and uPAR has been shown to correlate with allograft rejection in human biopsies. However, the causal connection of uPA/uPAR in mediating transplant rejection and underlying molecular mechanisms remain poorly understood. In this study, we evaluated the role of uPA/uPAR in a mice model for kidney ischemia reperfusion (IR) injury and for acute kidney allograft rejection. uPAR but not uPA deficiency protected from IR injury. In the allogenic kidney transplant model, uPAR but not uPA deficiency of the allograft caused superior recipient survival and strongly attenuated loss of renal function. uPAR-deficient allografts showed reduced generation of reactive oxygen species and apoptosis. Moreover, neutrophil and monocyte/macrophage infiltration was strongly attenuated and up-regulation of the adhesion molecule ICAM-1 was completely abrogated in uPAR-deficient allografts. Inadequate ICAM-1 up-regulation in uPAR−/− primary aortic endothelial cells after C5a and TNF-α stimulation was confirmed by in vitro experiments. Our results demonstrate that the local renal uPAR plays an important role in the apoptotic and inflammatory responses mediating IR-injury and transplant rejection.

Urokinase-Type Plasminogen Activator Promotes Paracellular Transmigration of Neutrophils Via Mac-1, But Independently of Urokinase-Type Plasminogen Activator Receptor

“…These findings are in line with recent observations, given that protection of the postischemic cerebral microvasculature by moderate hypothermia was associated with reduced tissue activity of uPA. 8 Notably, expression of uPA was found to be down-regulated on renal I/R, and uPA deficiency (but not uPAR deficiency) did not affect postischemic proteinuria, 35,36 suggesting a tissue-specific involvement of uPA and uPAR in the pathogenesis of I/R injury. Moreover, it is worth to be noted that pharmacological blockade of endogenous plasminogen activation might potentially exert antifibrinolytic side effects, which might be fatal in situations such as myocardial infarction.…”

Urokinase plasminogen activator and receptor promote collagen-induced arthritis through expression in hematopoietic cells

“…18 Interleukin 1b (IL-1b) and tumor necrosis factor a (TNF-a) elicit expression and secretion of uPA by several cells, including monocytes, endothelial cells, and neutrophils. [19][20][21] The present study sought to determine the contribution of both uPA and uPAR to collagen-induced arthritis (CIA) in the highly ) mice that were backcrossed (8 generations) to the CIA-susceptible DBA/1J strain were injected intradermally at the base of the tail with 100 mg bovine collagen type II (CII) (Elastin Products) in complete Freund's adjuvant on day 1 and once again on day 21 as previously described. 1 Mice were evaluated for arthritis using an arthritic index macroscopic scoring system ranging from 0 to 4 (0 5 no detectable arthritis, 1 5 swelling and/or redness of paw or 1 digit, 2 5 2 joints involved, 3 5 3 joints involved, and 4 5 severe arthritis of the entire paw and digit).…”

Bβ15–42 Attenuates the Effect of Ischemia-Reperfusion Injury in Renal Transplantation

“…32 Male C57BL/6 were anesthetized with isoflurane. After median laparotomy, renal pedicles were dissected and a nontraumatic vascular clamp was applied for 27 minutes.…”