The Role of Toll-like receptors in Diabetic Nephropathy
Summary
This project will investigate the role of Toll-like receptor 2 and 4 in the pathophysiology of diabetic nephropathy
Supervisor(s)
Professor Carol Pollock, Dr Usha Panchapakesan
Research Location
Kolling Institute of Medical Research
Program Type
PHD
Synopsis
Diabetic nephropathy is the leading cause of chronic kidney disease (CKD) globally and continues to grow in incidence and prevalence in parallel with the pandemic of Type 2 diabetes.Between 20-40% of those with diabetes develop progressive nephropathy leading to Stage 5 CKD requiring dialysis or transplantation, unless the course is interrupted by premature patient death. The pathogenesis of DN remains incompletely understood and consequently specific therapies are lacking. Best available management, which includes tight control of blood pressure and blood glucose plus renin-angiotensin axis inhibition, provides a reduction in the rate of progression of around 30% only. The burden of this disease on individuals and societies is enormous and growing rapidly. Although historically considered as a largely ‘non-inflammatory’ disease process, it has been recently demonstrated that inflammatory processes play a significant role in the development and progression of DN. Resident kidney cells and infiltrating monocytes secrete proinflammatory cytokines which contribute to the development of progressive renal disease. The kidney proximal tubule cell secretes several proinflammatory cytokines and chemokines, for example MCP-1, in response to hyperglycaemia. Indeed vaccination against cytokines such as CCL2/MCP-1 mitigates against diabetic renal injury in murine STZ induced diabetes. The importance of TLRs in the initiation and perpetuation of the inflammation of DN is not known. As TLR2 and 4 initiate inflammation via NF-kB, this would support the notion that TLRs contribute to the inflammatory component of DN, which in turn is involved in the progression of disease. Given this, we hypothesise that TLR2 and 4 activation by endogenous ligands is an initiating event in the pathogenesis of DN, providing a mechanistic link between hyperglycaemia and hypoxia with inflammation and fibrosis within the kidney. Hence, therapeutic interventions aimed at targeting the inflammatory component through interruption of TLR signalling may be a novel strategy to target for the prevention and treatment of DN. OUTCOME AND SIGNIFICANCE DN is the leading cause of chronic kidney disease. Comprehension of the mechanisms involved in DN is a major health priority and a pre-requisite for designing specific therapies to enable better management of this problem. Awareness of the importance of TLRs in “sterile inflammation” and subsequent pathological responses is growing rapidly. Substantial efforts in designing methods to suppress aberrant TLR-mediated responses are underway, targeting TLRs and ligands. If we delineate a significant role for TLR activation in the pathogenesis of DN, this would both advance global understanding of the mechanisms driving this disease and, of equal importance, would identify novel therapeutic targets. Such results would be of significant relevance to the many other disorders of kidney, and of other organs, where non-immune injury leads to a deleterious immune response, culminating in progressive organ injury.
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Keywords
toll-like receptor, diabetic nephropathy, inflammation, Fibrosis
Opportunity ID
The opportunity ID for this research opportunity is: 898
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