Associate Professor David Vesey

Modulating inflammatory and fibrogenic pathways in kidney disease using a novel antagonist of protease-activated-receptor-2

Background: The pathological processes of inflammation and fibrosis are evident in all forms of chronic kidney disease (CKD), and if not effectively treated will invariably progress to end stage renal failure when dialysis or organ transplantation are required for survival. This is extremely costly. As 1 in 10 Australians now show one or more signs of CKD and the prevalence of this condition is increasing at 6% per annum, it places an enormous strain on the health care system [1]. Current medications have not significantly impacted disease trends. Developing more effective therapies that specifically target these pathogenic processes are thus urgently needed. In this project we are investigating the efficacy of a novel experimental drug, GB88, developed by the group of Professor Fairlie, at The University of Queensland IMB. This drug specifically targets a protease sensing G-protein coupled receptor (GPCR) called protease-activated receptor-2 (PAR2), which is highly expressed by the kidney. This is the first truly potent, selective and bio-available PAR2 antagonist so far produced with the real possibility that it will be developed as drug treatment for inflammatory diseases. The fact that PAR2 knockout (KO) mice remain healthy and are also protected in models of kidney disease validates PAR2 as an important therapeutic target. The next logical step is to determine if therapeutic blockade of this receptor will deliver the same benefits as seen in the PAR2 KO mouse. Our research to date shows that GB88 effectively antagonises PAR2-induced inflammation in cultured kidney cells and in rodent models of arthritis and colitis significantly reduces disease severity.

AIMS: Three different, well-established and clinically-relevant animal models of kidney disease that exhibit distinct mechanisms of renal inflammation and fibrosis will be used to test whether GB88 can ameliorate:

1. Immune mediated renal disease (anti-glomerular basement membrane (GBM) disease) in which acute & chronic inflammation are mediated predominantly by infiltrating immune cells.
2. Obstructive kidney disease - unilateral ureteric obstruction (UUO). This is characterised by rapid & extensive renal fibrosis involving myofibroblast accumulation and matrix production.
3. Metabolic kidney disease - Streptozotocin-induced diabetic nephropathy (STZ-DN). This is a slower developing disease showing features of human diabetic nephropathy with involvement of both infiltrating immune cells and intrinsic renal cells.