understanding
the development of
renal failure
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In the body, hormones and hormone-like agents pass messages between cells and organs. These messages can either maintain health or, in disease states, aggravate the disease.

The hormones and hormone-like agents act on the outside of cells. The cells interpret the messages and react by producing complex networks of signal pathways inside the cell.

Because a single hormone or agent can induce a wide variety of outcomes, it is important that we identify the different signals inside the cell that regulate the different outcomes.

To this end, Lecturer Dr Mark Dockrell is supervising the work of Research Fellows Dr Simon Winn, and Dr Nilesh Shah into the causes of Renal Interstitial Fibrosis(scarring of the kidneys) and collaborating with the work of Dr Mysore Phanish.

We know that continued scarring will eventually lead to chronic kidney disease.

Therefore, the research is aimed at finding out not only what causes the scarring but a way to safely stop, or considerably slow down, the formation of this damaging scar tissue.

 

Dr Mysore Phanish performed his PhD studies at SWTIRR under the supervision of Dr Dockrell and Professor Bruce Hendry of King’s College London from 2002-2005. He gained his medical degree from Jawaharlal Nehru Medical College, Karnataka University, Dharwar, India. He was awarded gold medals for first rank to the University in his 2nd and final year MBBS aDr Mysore Phanishnd for obtaining first rank to the University in General Medicine. He was awarded the Pfizer Postgraduate Medical Award & Medal by Pfizer Pharmaceuticals Ltd for the year 1991 and the Dr R R Joshi Gold Medal for best outgoing medical student of Karnataka University, India, awarded by the Indian Medical Association for the year 1992.

After obtaining his medical degree (MBBS) in 1992, he obtained an MD degree in General Medicine from one of the premier medical institutions of India, the Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh in 1996. He trained in Nephrology at the University Hospital of Wales, Cardiff, Bangor District General Hospital, St Helier Hospital and Guy’s Hospital, London. Dr Phanish is currently a consultant nephrologist at the St Helier Hospital, Epsom and St Helier University Hospitals NHS trust and Mayday University Hospital NHS Trust and Honorary Senior Research Fellow at SWTIRR.

Connective Tissue Growth Factor (CTGF CCN2) is a more recently identified protein that promotes scarring within the kidney. It is both a marker and mediator of kidney scarring. During his work at SWTIRR Dr Phanish was the first to identify CTGF production from human proximal tubule epithelial cells (PTECs). He later went on to dissect various cell signalling pathways that regulate the production of CTGF. He also studied cell signalling pathways regulating transition of tubule epithelial cells to scar producing myo-fibroblasts. The results from this work were published in peer-reviewed journals (Nephron-experimental nephrology and Biochemical Journal). He has also presented his work in several national and international renal meetings.

Dr. Phanish’s current work aims to investigate the effects of CTGF on human proximal tubule epithelial cells. He intends to investigate the mechanisms of pro-fibrotic effects of CTGF on human PTECs. In addition, he has recently obtained a grant from Johnson and Johnson (as a co-applicant with Dr. Dockrell) to study urinary markers in diabetic kidney disease.

 

Dr Simon Winn: In 2006 Dr Phanish published the first report of the powerful pro-fibrotic agent Dr Simon WinnCTGF being produced in epithelial cells. As part of his own PhD work at SWTIRR with Mark Dockrell, Dr Phanish had investigated the production of CTGF in the kidney with it implications for fibrosis and the associated kidney disease. This work was very successful and Phanish was awarded his PhD from the University of London in 2008; yet his work had generated as many new questions as answers. Dr Simon Winn arrived at SWTIRR in October 2008 to continue this work and try and find some of these answers. Under the supervision of Phanish and Mark, Simon is working towards a PhD studying the affects of CTGF on the cells that line the tubes of the kidney, the Proximal Tubule Epithelial Cells or PTECs.

Work from SWTIRR has highlighted the importance of the PTEC in kidney failure and this project expands on this by investigating whether the PTEC is both a source and a target for the actions of CTGF. Connective Tissue Growth Factor, CTGF, was identified in the 1990s and has since been demonstrated to be involved in a range of diseases including: keloids, lung fibrosis, liver cirrhosis, pancreatic fibrosis, atherosclerosis, myocardial fibrosis, cataracts and, importantly for us, diabetic renal fibrosis. What we still do not know is exactly how CTGF acts and how we might be able to control it. We do know that CTGF has a positive role in wound healing and we also know that the fibrotic diseases display a type of faulty tissue regeneration and hence CTGF may be a key player in changing the balance between healthy wound healing and potentially fatal fibrosis.

Simon will seek to generate CTGF from human PTEC, purify and then administer it to fresh cells. He is hoping to identify how it regulates scar production, which is the hall mark of fibrosis, cell death and the response of the cells to other agents that may also be involved in the regulation of renal fibrosis. Although SWTIRR has considerable expertise in studying PTEC and their role in fibrosis this project is going to be strengthened by the close collaboration with Dr Maria Fragiadaki and Professor Roger Mason of Imperial College who is an expert in CTGF and diabetic renal disease.

 

Dr Nilesh Shah: The wall of the nephrons, the functional working units of the kidney, is madeDr Nilesh Shah up of specialised epithelial cell held together by a number of different proteins which help form a continuous epithelium and attach it to the basement membrane. One family of proteins, the cadherin proteins, are widely expressed through out the body but different members of the family are expressed in the different epithelia. When the kidney becomes injured and starts to fail the cadherin expression changes, the nephron degenerates, the epithelial cells of the tubule are no longer held together, many cease to function properly and some cells die.

Dr Nilesh Shah is studying the members of the cadherin family that are expressed in the proximal tubule of the human nephron and investigating how their expression changes in disease and how this contributes to the acceleration of renal fibrosis; the scarring process that leads to kidney failure. Many groups use animal models of kidney disease to investigate fibrosis but Nilesh’s preliminary data support the hypothesis that the cadherins expressed in the human proximal tubule differ from that in rat and mouse.

This project is being performed in collaboration with Dr Roel Goldschmeding and Dr Tri Q. Nguyen of the University Medical Center Utrecht, in the Netherlands due to their extensive expertise in the pathology of human renal disease, particularly tubulo-interstitial fibrosis. With our collaborators Nilesh has been able to show the expression of specific cadherins in human biopsy material and match them up with those expressed in the human cell cultures in the laboratory. This has allowed him to investigate which are mediating cell cell adhesion and which are holding the cells to the basement membrane. Then using different models of kidney injury he is studying what happens to the cadherins.

We also know that cadherin proteins are more than just “anchors” but they also regulate the activation of signalling molecules that can then regulate how the cell behaves. Nilesh intends to selectively investigate the role of the cadherins and the signalling pathways they activate.

 

Dr James Browne completed his BSc at the University of Surrey in 2004 and his MSc in 2005. Previously, James had worked at SWTIRR in his sandwich year during his degree. James returned in October 2005 as the Epsom & St. Helier University Hospitals NHS Trust Research and Development Research Fellow to work with Dr Dockrell studying Erk5 activation in human proximal tubule cells.

Previously Dr Dockrell’s team were among the first groups to show the signalling molecule Erk5 existed in human proximal tubule epithelial cells and that it could be activated by the pro-fibrotic growth factor TGF-beta. This project expands that work to investigate whether Erk5 may have a role in the development in renal fibrosis and will also examine a potential role for Erk5 in diabetic nephropathy.