Diabetic Nephropathy

Diabetes is linked to multiple secondary complications including diabetic nephropathy, the leading cause of End Stage Renal Disease (ESRD). Almost one third of all patients with diabetes progressively develop diabetic nephropathy within 10-to-30 years of the onset of disease.

Transforming growth factor beta (TGF-β) is a pro-fibrotic cytokine elevated in response to high concentrations of circulating glucose. The cytokine is thought to be the predominant mediator of tubulointerstitial fibrosis, a common final pathway in diabetic nephropathy and ESRD. Therefore, understanding the mechanism by which TGF-β instigates phenotypic and morphological changes in renal epithelia is essential to establish novel therapeutic strategies for the prevention or arrest of the disease.


Photo: Glucose and TGF-b1 and induce morphological, fibrotic changes in human kidney proximal tubule cells.

Professor Paul Squires and Dr Claire Hills are interested in several aspects of glucose and TGF-beta induced renal damage in diabetes. Our studies examine how TGF-β disrupts cell-adhesion, cell-cell communication and renal function in diabetic nephropathy.


1) The role of the extracellular matrix and cell-substrate interactions in the diabetic kidney

The Extracellular Matrix (ECM) has a crucial role in maintaining appropriate cell function and interacts with cell surface proteins to provide an anchor to the cell cytoskeleton as well as directly regulating numerous cell-signalling events.

Left photo: Cytoskeletal staining (red) of an epithelial cell isolated from the human collecting duct.

Modification and/or remodelling of the ECM can severely impact on renal function and has been linked to various forms of kidney disease, including diabetic nephropathy. In our laboratories we utilise human primary kidney cells and kidney biopsy tissue obtained from patients with diabetic nephropathy, to better understand the mechanisms by which glucose and TGF-b1 modify cell behaviour as a consequence of ECM remodelling.

Using an array of sophisticated laboratory techniques, we are specifically interested in; how changing the composition of the extracellular matrix, i.e. the cells microenvironment, not only regulates the ability with which these cells interact with each other, but also how the cells respond to pathophysiological changes in their extracellular environment, e.g. in response to high glucose seen in diabetic nephropathy.


Diabetes922Right photo: AFM single-cell force spectroscopy. A single cantilever bound cell is bought in to contact with either an adherent kidney cell or a range of substrates to assess cell-cell and cell-substrate interactions in response to pathophysiological stimuli including glucose and TGF-b1 (Image courtesy of JPK instruments

This research is funded by a European Foundation for the Study of Diabetes (EFSD) and Diabetes UK research grant to Dr Claire Hills & Prof. Paul Squires,and a research grant from DRWF to Dr. Claire Hills.


2)The role and regulation of connexin mediated Gap Junctions in the progression of renal fibrosis

We are investigating how cells in the diabetic kidney, utilize gap-junctions in their cell membrane to coordinate renal function. Kidney cells normally form a highly coupled epithelial sheet, held together by an adhesion molecule called epithelial (E)-cadherin (ECAD).

We have previously demonstrated that cell adhesion is a pre-requisite for an efficient conversation between cells, and that loss of this adhesion, is likely to facilitate loss of of synchronised cell communication and the development of early changes that underline the onset of diabetic nephropathy. Having developed a physiologically appropriate model cell system of the relevant section of the kidney at risk, we are investigating how cell-to-cell communication changes in response to high levels of glucose and increased TGF-b1. 

This research was funded by Diabetes UK grants to Prof. Paul Squires & Dr. Claire Hills.


P‌hoto: Schematic demonstrating epithelial (E)-cadherin ligation and connexon alignment in the formation of gap-junctions in epithelial cells of the renal proximal tubule.


3) The downstream pro-fibrotic actions of immunosuppressant Cyclosporin A

Diabetic nephropathy accounts for almost a quarter of those entering end-stage renal replacement programs in the UK. Cyclosporin A (CsA), is an immunosuppressant drug used to improve graft survival in renal transplantation, however, its widespread use can be marred by associated nephrotoxicity.

Preliminary studies confirm that exposure of renal tubular cells to CsA evokes morphological and phenotypic changes characteristic of early tubular injury. Ultimately, transplant patients with diabetes placed on CsA may develop tubulointerstitial fibrosis of the newly transplanted kidney, a process associated with loss in expression of epithelial markers and gain in expression of those more commonly associated with a fibroblast phenotype.

The transition of cells to an intermediate cell phenotype in response to high concentrations of CsA is likely to represent the underlying pathology of secondary fibrosis in patients post transplant. Our work on CsA in the proximal tubule aims to identify the relationship between CsA and the expression of candidate proteins central to cell adhesion, cell matrix interaction and ultimately increased fibrotic deposition in the newly transplanted kidney. 

This research is funded as a PhD Studentship from the Petroleum Technology Development Fund.


Diabetes Funding

All research is funded by EFSD, The Physiological Society and Diabetes UK:

Diabetes UK

EFSD Psociety

School of Life Sciences, University of Lincoln, Brayford Pool, Lincoln. LN6 7TS 

email: enquiries@lincoln.ac.uk
tel: + 44 (0)1522 886654