Renal, diabetic and hypertensive disease

 

What

These important disease conditions and the cardiovascular system are closely inter-related. Renal disease is a major risk factor for cardiovascular disease and predisposes to hypertension. Conversely renal disease may result from both hypertension and other cardiovascular diseases including atherosclerosis.

Complications of diabetes result from the damage to the cardiovascular system. This may be macrovascular disease such as atherosclerosis or microvascular disease contributing to nephropathy, neuropathy and cardiomyopathy. Hypertension results from a complex interaction of genetic and dietary factors along with dysfunction of the autonomic nervous system and other contributors including renal disease and diabetes. Its consequences include widespread vascular damage.

Renal research focuses on diseases of the glomerulus which result in proteinuria. The commonest of these is diabetic nephropathy which is the leading cause of renal failure in the UK and accounts for 1% of NHS expenditure. Recent work on endothelial glycocalyx dysfunction is of particular interest as it may provide the missing link between proteinuria and cardiovascular disease.

Work on diabetes includes studies of the mechanisms and consequences of diabetic nephropathy, focusing on insulin signaling pathways, the role of vascular endothelial growth factors and the endothelial glycocalyx. Other studies include diabetic cardiomyopathy, effects of diabetes of bone marrow endothelium and limb ischaemia and vascular repair mechanisms in diabetes.

Work on hypertension focuses particularly on the involvement of the autonomic nervous system and includes investigation of organ blood flow and renal denervation.

Where

Research is conducted mostly by people in the School of Clinical Sciences and the School of Physiology and Pharmacology, and is based in the Dorothy Hodgkin building, Medical Sciences Building and in Bristol Royal Infirmary (level 7).

How

We study the specialised cells of the glomerular filtration barrier, glomerular endothelial cells and podocytes, to understand their behaviour in health and disease. We use sophisticated models incorporating co-culture and shear stess and use a range of molecular, biochemical and imaging techniques. Cell lines we have generated form the basis of scores of international collaborations.

In vivo models of disease include type 1 and type 2 diabetes and transgenic models are used to dissect insulin signalling pathways and VEGF pathobiology. Ex vivo imaging of the glomerulus and in vivo imaging of the microcirculation are important techniques.

In vivo models and advanced functional monitoring techniques are also used to study the role of the autonomic nervous system in regulation of hypertension. 

Highlights

Example publications include:

Insulin signaling to the glomerular podocyte is critical for normal kidney function.
Welsh GI, Hale LJ, Eremina V, Jeansson M, Maezawa Y, Lennon R, Pons DA, Owen RJ, Satchell SC, Miles MJ, Caunt CJ, McArdle CA, Pavenstädt H, Tavaré JM, Herzenberg AM, Kahn CR, Mathieson PW, Quaggin SE, Saleem MA, Coward RJCell Metab. 2010 Oct 6;12(4):329-40

Loss of the endothelial glycocalyx links albuminuria and vascular dysfunction.
Salmon AH, Ferguson JK, Burford JL, Gevorgyan H, Nakano D, Harper SJ, Bates DO, Peti-Peterdi J. J Am Soc Nephrol. 2012 Aug;23(8):1339-50

VEGF165b overexpression restores normal glomerular water permeability in VEGF164-overexpressing adult mice.
Oltean S, Neal CR, Mavrou A, Patel P, Ahad T, Alsop C, Lee T, Sison K, Qiu Y, Harper SJ, Bates DO, Salmon AHAm J Physiol Renal Physiol. 2012 Oct;303(7):F1026-36.

Glycosaminoglycan regulation by VEGFA and VEGFC of the glomerular microvascular endothelial cell glycocalyx in vitro.
Foster RR, Armstrong L, Baker S, Wong DW, Wylie EC, Ramnath R, Jenkins R, Singh A, Steadman R, Welsh GI, Mathieson PW, Satchell SCAm J Pathol. 2013 Aug;183(2):604-16.

Initial Steroid Sensitivity in Children with Steroid-Resistant Nephrotic Syndrome Predicts Post-Transplant Recurrence.
Ding WY, Koziell A, McCarthy HJ, Bierzynska A, Bhagavatula MK, Dudley JA, Inward CD, Coward RJ, Tizard J, Reid C, Antignac C, Boyer O, Saleem MAJ Am Soc Nephrol. 2014 Feb 7. [Epub ahead of print].

Ongoing projects include:

  • Role of GSK proteins in insulin signalling and diabetic nephropathy
  • Studying the mechanisms of focal segmental glomerulosclerosis including the role of the ion channel TRPC6
  • Role of endothelial glycocalyx dysfunction in diabetic nephropathy and cardiomyopathy
  • Role of laminar shear stress, KLF2 and shear-regulated microRNAs in cell-cell communication in the vascular wall
  • The beneficial effects of VEGF-C in diabetic nephropathy using transgenic podocyte-specific VEGF-C overexpression
  • Systemic endothelial glycocalyx damage in nephrotic syndrome
  • The role of VEGF splicing isoforms and alternative splicing in general in diabetes and diabetic nephropathy

People

Further details on research in renal, diabetic and hypertensive disease can be found by visiting pages of key researchers in this field

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