Renal
Dr Jonathan H. Erlich
The Renal research group led by Dr Erlich is based in the Prince of Wales Hospital. The main focus of the group has been investigations of the protease coagulation cascade, protease activated receptor (PAR) signaling, and the contribution of these factors to acute and chronic inflammation in renal disease. Renal ischaemia reperfusion (IR) injury is an important clinical problem that may occur in association with acute renal failure and following renal transplantation. In organ transplantation renal IR is now recognized as an important contributor to delayed graft function and increased risk of chronic allograft nephropathy, leading to premature graft loss and return to dialysis. Identification of factors leading to reduction or prevention of reperfusion injury is likely to have significant clinical benefits.
We have utilized pharmacological intervention in genetically modified mice to examine the role of the tissue factor-thrombin-PAR-1 system and its contribution to renal IR injury. Our studies have shown that inhibition of thrombin with a specific thrombin inhibitor, hirudin, and deficiency of tissue factor (TF) or PAR-1 leads to improved outcome in mice undergoing renal IR injury. This effect is at least in part due to reduced neutrophil infiltration and CXC-chemokine expression, and possibly reduced apoptosis. As these changes are largely independent of fibrin, non-anticoagulant strategies may potentially be useful to reduce renal IR injury.
We have tested this hypothesis by using a PAR-1 inhibitor (SCH79797) that does not affect activation of coagulation and shown this to be an effective strategy to reduce renal ischaemia reperfusion injury. This providing direct evidence that a pharmacological strategy to modify the TF-PAR-1 system can be achieved with out affecting activation of coagulation.
More recently we have shown that the cytoplasmic domain of the TF molecule can be anti-inflammatory. Mice with a deficiency of the cytoplasmic domain of TF developed relatively more severe renal IR injury. This was in association with increased PAR-1 expression. Blockade of PAR-1 with a pharmacological approach reduced their renal injury to levels similar to that in wild type mice.
Recent studies have suggested a role of PAR-1 in activation of the sphingosine-1 phosphate receptors (SIPr). There are at least 5 SIP receptors that upon activation provide a wide variety of pro and anti-inflammatory effects as well as an ability to regulate T cells trafficking. The ability of PAR-1 activation to produce differential effects according to the pattern of SIP receptor activation provides an important new avenue of investigation and potential therapeutic opportunities.
During 2007 we have looked at other potential mechanisms by which PAR-1 may regulate renal IR. PAR-1 at least in part regulates the antiangiogenic molecule thrombospondin expression that has been shown to be an important effector system in renal IRI.
In a model of chronic renal injury we demonstrated that PAR-1 contributed to the regulation of epithelial to mesenchmyal transformation (EMT). As mice expressing low TF and therefore have reduced thrombin production were not similarly protected this suggested that thrombin mediated activation of PAR-1 per se was not essential to the development of renal scaring and some other PAR-1 dependent system was operative. MMMP-1 and plasmin have been suggested as other biologically relevant activators of PAR-1. Our data suggested the mouse homologue of MMP-1 was not increased and taken with recent studies of other showing plasmin may activate PAR-1 suggests at least in part plasmin may be acting via PAR-1
Our mouse heart studies have shown that TF may regulate postnatal angiogenesis in a sex dependent manner. Prepubertal (4week old male) low TF mice displayed reduced levels of myocardial visualization in association with reduced angiopoeitin (Ang) -2 and VEGF compared to WT mice. ANG-2 and VEGF are recognized as critical growth factors for postnatal angiogenesis. Female low TF and WT mice at the same age showed no significant differences.