Associate Professor David Vesey

BSc, PhD

Senior Scientist

Projects

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.
Protease Activated Recptor-2 (PAR2) in kidney disease

About me

David graduated from the University of London with a BSc (Hons) in biochemistry (King’s College) and PhD which investigated the role of epidermal growth factor receptors in liver regeneration (Imperial College). Since then he has worked on a variety of projects including; immunoassay develoment (Ortho Clinical Diagnostics); R & D of an artificial liver machine (Imperial College); and p53 mutations in liver cancer (QIMR). He joined the Department of Nephrology at the Princess Alexandra Hospital in Brisbane in 1999. He is an Associate Professor at The University of Queensland Faculty of Medicine, a senior member of the UQ Center for Kidney Disease Research and manages the Princess Alexandra Hospital Endotoxin Testing Service.

His main research interests are in the area of renal tubulointerstitial fibrosis, inflammation and also the mechanisms of renal cancer development – particularly the role that cytokines and growth factors play in these processes. Current projects include the role of protease activated receptor-2 in renal scarring, inflammation and cancer and the mechanism of heavy metal toxicity in the kidney. The Princess Alexandra Hospital Endotoxin Testing Service routinely tests samples from dialysis units throughout Queensland.

Publications

  1. Suen JY, Cotterell A, Lohman RJ, Lim J, Han A, Yau MK, Liu L, Cooper MA, Vesey DA, Fairlie DP. Pathway-selective antagonism of proteinase activated receptor 2.Br J Pharmacol. 2014 171:4112-24.

  2. Morais C, Small D, Vesey DA, Martin J, Johnson D, Gobe G. Fibronectin and transforming growth factor beta contribute to erythropoietin resistance and maladaptive cardiac hypertrophy. Biochem Biophys Res Commun 444:332-7, 2014

  3. Carneiro MFH, Morais C, Small D, Vesey DA, Barbosa F Jr, Gobe G. Thimerosal Induces Apoptotic and Fibrotic Changes to Kidney Epithelial Cells In Vitro. Environmental Toxicology (Accepted June 20 14)

  4. Rossi M, Campbell K, Johnson DW, Stanton T, Vesey DA, Coombes J, Weston K, Hawley C, McWhinney B, Ungerer J and Isbel N. Uremic toxins, inflammation and oxidative stress: a cross-sectional study in stage 3-4 chronic kidney disease. Arch Med Res. 2014 Apr 18 [Epub ahead of print]
  5. Gobe G, Bennett N, West M, Colditz P, Brown L, Vesey DA, and Johnson DW. Increased progression to kidney fibrosis after erythropoietin is used as a treatment for acute kidney injury. Am J Physiol Renal Physiol 306:F681-92, 2014
  6. Cho Y, Johnson DW, Vesey DA, Hawley CM, Pascoe EM, Clarke M, Topley N.  Utility of urinary biomarkers in predicting loss of residual renal function:  the balANZ trial.  Perit Dial Int, Apr 7. [Epub ahead of print]
  7. Cho Y, Johnson DW, Vesey DA, Hawley CM, Pascoe EM, Clarke M, Topley N.  Baseline serum interleukin-6 predicts cardiovascular events in incident peritoneal dialysis patients.  Perit Dial Int, Apr 7. [Epub ahead of print]
  8. Cho Y, Johnson DW, Vesey DA, Hawley CM, Pascoe EM, Clarke M, Topley N.  Dialysate interleukin-6 predicts increasing peritoneal solute transport rate in incident peritoneal dialysis patients.  BMC Nephrol, 15:8 2014
  9. Cho Y, Johnson DW, Vesey DA, Hawley CM, Pascoe EM, Clarke M, Topley N.  Higher dialysate matrix metalloproteinase-2 levels are associated with peritoneal membrane dysfunction.  (Perit Dial Int Under Review March 2014).
  10. Suen JY, Cotterell A, Lohman RJ, Han, A, Lim J, Yau MK, Liu L, Vesey D A, Cooper MA, Fairlie DP. Pathway Selective Antagonism Of Proteinase Activated Receptor 2.Br J Pharmacol. 2014 May 12 [Epub ahead of print]
  11. Vesey DA, Suen J, Seow V, Lohman R-J, Liu L, Gobe G, Johnson DW, Fairlie DP. PAR2-induced inflammatory responses in human kidney tubular epithelial cells. Am J Physiol Renal Physiol. 304:F737-50, 2013
  12. Gobe GC, Morais C, Vesey DA, Johnson DW: Use of high-dose erythropoietin for repair after injury: A comparison of outcome in heart and kidney. Journal of Nephropathology 2:154-165. 2013
  13. Morais C, Johnson DW, Vesey DA, Gobe GC. Functional Significance of Erythropoietin in Renal Cell Carcinoma. BMC Cancer 10:13-14. 2013
  14. Bennett NC, Hooper JD, Lambie D, Lee CS, Yang T, Vesey DA, Samaratunga H, Johnson DW, Gobe GC.. Evidence for Steroidogenic Potential in Human Prostate Cell Lines and Tissues. Am J Pathol. 2012 181(3):1078-87
  15. Rajandram R, Bennett NC, Wang Z, Perry-Keene J, Vesey DA, Johnson DW, Gobe GC. Patient samples of renal cell carcinoma show reduced expression of TRAF1 compared with normal kidney and functional studies in vitro indicate TRAF1 promotes apoptosis: potential for targeted therapy. Pathology 44: 453–459. 2012.
  1. Lohman R-J, Cotterell AJ, Grant DB, Liu L, Suen JY, Vesey DA, Fairlie DP. An antagonist of human protease activated receptor-2 attenuates PAR2 signaling, macrophage activation, mast cell degranulation, and collagen-induced arthritis in rats. FASEB J. 26:2877-87. 2012.
  1. Lohman R-J, Cotterell AJ, Suen J, Liu L, Do TA, Vesey DA, Fairlie DP. Oral administration of a novel PAR2 antagonist protects against experimental colitis in rats. J Pharmacol Exp Ther. 340:256-65. 2012

Research fields

Kidney disease