Dr Tim Johnson BSc PhD
Reader in Nephrology
Academic Unit of Nephrology
Department of Infection and Immunity
Sir Henry Wellcome Laboratories for Biomedical Research
The University of Sheffield Medical School
Beech Hill Road
After completing my PhD at Nottingham Trent University I joined the University of Sheffield in 1993 as the first Sheffield Kidney Research Fund sponsored Post Doctoral Scientist. My role was to work alongside Professor Meguid El Nahas and Dr John Haylor to help develop a molecular biology dimension to their work in kidney fibrosis. In 1996 I started to investigate my own interets in the area looking at the role of the Matrix metalloproteinases and especially Transglutaminase type 2 in chronic kidney disease.
In 2000, I was awarded a National Kidney Research Fund (Now Kidney Research UK (KRUK) Senior Fellowship and, supported by additional funding from The Wellcome Trust, KRUK and Diabetes UK, established what has become the Tissue Scarring and ECM Processing Research Group within the Academic Nephrology Unit.
In 2005 I was awarded a lectureship in the Medical School and promoted to Senior Lecturer in 2007, and Reader in 2010. I have a keen interest in translational research and in particular developing our lab discoveries for clinical application. To this end, good collaborations have been established with several major biotechnology and pharmaceutical companies.
I currently work in the area of kidney fibrosis, including complications of this disease such as encapsulating peritoneal sclerosis resulting from peritoneal dialysis. I concentrate in the areas of transglutaminase 2, matrix metalloproteinases and the plasmin system with studies aimed at understanding pathobiology, methods of intervention and diagnostic biomarkers.
Transglutaminase in Kidney Fibrosis:
This is the primary area of research for my group. We have previously described an upregulation and cellular export of transglutaminase 2 (TG2) in chronic kidney disease and correlated this to human disease including chronic allograft nephropathy post transplant. We have also shown that broad spectrum TG inhibitors can block kidney scarring and that the TG2 knockout mouse is resilient to the disease. We have established the mechanism of TG2 in causing kidney fibrosis, both in terms of its modification of ECM processing and its role in the activation of TGF beta 1. Current projects are looking at how TG2 is exported from the tubular epithelial cells during disease to see if this is a possible intervention area. Much of this is being done in collaboration with Eli Verderio Edwards at Nottingham Trent University with a joint Wellcome Trust award to look at the role of Syndecan 4 in this process. Our other main area is developing anti TG2 therapeutics for clinical application. The two main areas here are designing blocking antibodies in collaboration with MRC-T and developing a class of natural anti TG inhibitors in collaboration with Pfizer Pharmaceuticals.
The Matrix Metalloproteinases in Kidney Fibrosis:
Work here is looking at the changes in the matrix metalloproteinase (MMP) family and their inhibitors; tissue inhibitor of MMP (TIMP) in the scarring process. The group has demonstrated that in kidney scarring it is predominantly the over expression of TIMP 1 that shuts down MMP activity with many MMPs being over expressed in disease. Further, using an in situ zymography technique that compartmental regulation and separation of MMPs and TIMPs is critical for function and that whole tissue studies are very misleading. Current studies are aimed at establishing if these findings are similar across a range of human diseases as these data would have a profound effect on potential targets in chronic kidney disease.
The Plasmin System in Kidney Fibrosis:
For many years a low kidney plasmin level has been associated with a low ECM clearance and thus the development of kidney scarring. The plasmin activator inhibitor 1 knockout mouse demonstrated the importance of maintaining high plasmin levels, but pharmaceutically this has been difficult. Recent work by Pfizer has led to the development of a Tissue Activated Fibrinolytic Inhibitor (TAFI) blocker which could potentially be used to raise plasmin levels by keeping fibrin in a form that is good as a co-factor for plasmin activation. Work in the lab has demonstrated that the use of TAFI inhibitor in cell culture models raises plasmin activity and has a marked effect on ECM levels in epithelial, mesangial and fibroblast kidney lines. Next step is to see what happens in vivo!
Encapsulating Peritoneal Sclerosis (EPS):
EPS is a potentially fatal complication of peritoneal dialysis (PD), affecting about 2% of patients on PD. It is characterised by a rapid cocooning of the bowel leading to gut immobilisation. It is unclear what the disease process is, what triggers it and whether it is an advancement of the continual peritoneal sclerosis see in PD patients or a totally independent process. Working as part of a multicenter study (Cardiff, Stoke, Manchester) funded by Baxter Healthcare using samples from the global study, we are performing proteomics studies comparing effluent samples from those who develop EPS to those that do not over the period of dialysis. In conjunction with this, we are also adopting a more classical approach by examining levels of known fibrotic molecules across the 200 plus samples we have available, to isolate any changes in patients who go on to develop EPS. Ultimately we hope to identify the pathobiology, select intervention targets for therapy but importantly pick up early markers of EPS so PD can be stopped before complications develop.
Biomarkers of Chronic Kidney Disease:
Early and better identification of the stage of chronic kidney disease (CKD) and an ability to identify progressive disease would not only have a profound effect on treating CKD but would allow quicker and thus realistic trials in CKD to be performed aiding the development of therapeutics. We have established a large bio bank of urine and serum samples from 100s of patients in Sheffield with the assistance of Pfizer, and we are using a systematic approach to establish if any of the known mediators of CKD, or molecules identified from proteomics, can be detected in the urine and if these predict the advancement / development of disease. Using a combination of ELISA, protein arrays and amino acid analysis, potential markers are readily being identified.
- MSc / Diploma Nephrology. Research Skills in Science & Medicine (Module leader)
- Phase 1b Medical Students. Pathology of Renal Scarring
- Postgraduate Students RTP. MED6950 - Literature Review (RTP leader)
- Postgraduate Students RTP. MED6960 – Research Skills (RTP leader)
- MMB334 Biochemical basis of Disease. (Renal Scarring / ECM homeostasis / Diabetic Nephropathy / Transplantation)
- Associate Editor, Nephron Experimental Nephrology June 2007 –
- Renal Association, National Executive Member (Elected) April 2006 – May 2009
- Renal Association, Chairman – Renal Scientist Working Party May 2006- April 2009
- Renal Association, Past Chairman – Renal Scientist Working Party May 2009- April 2010
- Renal Association Annual Meeting Programme Committee 2006, 2007, 2008, 2009
International invited lectures
- Gordon Research Conferences; Transglutaminase in Human disease. Transglutaminase type 2: A hot therapeutic target in Chronic kidney Disease. North Carolina, USA. 18 to 23 July 2010
- European Renal Association & European Dialysis & Transplantation Association joint annual conference. Controlling transglutaminase type 2 prevents the progression of chronic kidney disease. Munich, 24-28 June 2010.
- World Congress of Nephrology. Transglutaminase inhibition: A new therapeutic approach to the treatment of progressive kidney scarring. Singapore, 25th -30th June 2005
- European Renal Association. Symposia in Chronic Allograft Pathology. Is Transglutaminase the switch between inflammation and fibrosis in Chronic Allograft Nephropathy? Heidelberg 13th–15th February 2004.
- 7th BANFF Conference on Transplant Pathology. Is Transglutaminase the switch between inflammation and scarring in Chronic Allograft Nephropathy? Aberdeen, Scotland. 14-18th June 2003.
- 7th International Transglutaminase and Protein crosslinking reactions conference. Renal Disease: From the Bench to the Bedside. Ferrara, Italy. 14th September 2002. Minerva Biotechnologica, 14, (2); 189, 2002.
- European COST conference on Apoptosis and Effector Systems in cell death. Nottingham. May 2002. Transglutaminase mediated cell death in the Kidney.
- Renal Association (UK). Transglutaminase. The role of a protein super glue in renal scarring. Autumn Meeting, October 2001, Royal Collage of Physicians, London, UK.
- American Society of Nephrology Annual Meeting. Changes in Extracellular Matrix processing in Renal Scarring. Toronto, Canada. October 2000.
- VI International Conference on Transglutaminase and Protein Crosslinking Reactions. The Role of Tissue Transglutaminase in Diabetic Nephropathy. Lyon, France. September 2000.
- International symposium on Rapid opiate detoxification under anaesthesia or sedation and post detox management using Naltrexone, BONDS: A 5 day opiate detoxification regime using Naltrexone, Risk, Efficacy and Outcomes. Berlin, June 99.
- Experimental diabetic nephropathy can be ameliorated using transglutaminase inhibitors. Linghong Huang, John L. Haylor, Zoe Hau, Richard Jones, Martin Griffin, Robert E. Saint, Ian G.C. Coutts, A. Meguid El Nahas and Timothy S. Johnson. Kidney International. 2009 Aug;76(4):383-94 Jun 24. [Epub ahead of print].
- Modulation of tissue transglutaminase in tubular epithelial cells alters extracellular matrix levels: A potential mechanism of tissue scarring. Fisher M, Jones RA, Huang L, Haylor JL, El Nahas M, Griffin M, Johnson TS. Matrix Biol. 2009 Jan;28(1):20-31. Epub 2008 Nov 5.
- Localization of Matrix Metalloproteinases and Their Inhibitors in Experimental Progressive Kidney Scarring. Aimun K Ahmed A M El Nahas and Timothy S Johnson. Kidney International. 2007 Apr;71(8):755-63.
- Tissue Transglutaminase and the Progression of Human Renal Scarring. Timothy S Johnson, Ahmed F El-Koraie, N James Skill, Nahed M Baddour, A Meguid El Nahas, Melvin Njloma, and Martin Griffin. Journal of the American Society of Nephrology, 2003. 14(8):2052-62.
- The role of transglutaminase in the rat subtotal nephrectomy model of renal fibrosis. Timothy S Johnson, Martin Griffin, Graham L Thomas, James Skill, Ann Cox, Bin Yang, Ben Nicholas, Paul J Birckbichler, Chiwoneso Muchaneta-Kubara and Meguid A El Nahas. Journal of Clinical Investigation 1997, vol 99, no 12, 2950 - 2690.