Macrophages and diabetic nephropathy

Despite improvements in medical care, the incidence of diabetic kidney disease has rapidly increased and it is now the most common cause of kidney failure, necessitating dialysis or transplantation. It is therefore important that we identify novel treatments to prevent or retard the development of kidney disease in individuals with diabetes. Recent research indicates that chronic inflammation is an important feature of diabetic kidney disease and key inflammatory cells called macrophages are implicated in progression of the disease. The current research will examine whether kidney disease in diabetic mice can be prevented by administration of a toxin that specifically kills macrophages. In addition, as macrophages localise to injured kidneys, diabetic rats will be injected with genetically-modified macrophages that will deliver protective mediators specifically to the damaged kidneys. Finally, tissue culture experiments will be employed to determine how the abnormal proteins that accumulate in diabetic renal disease alter both pro-inflammatory and anti-inflammatory macrophage functions. By understanding the inflammatory pathways involved in diabetic kidney damage, we may be able to develop novel treatments.

Despite advances in glycaemic and blood pressure control, the incidence of diabetic kidney disease continues to rise such that it is now the single most common cause of end-stage renal failure in the western world. It is imperative, therefore, that novel strategies for the prevention and amelioration of diabetic nephropathy are developed, based on an improved understanding of the pathophysiology of the disease.

Recent research indicates that diabetic nephropathy exhibits features of chronic inflammation with accumulating evidence implicating macrophages in disease progression. Hence modulation of inflammation and macrophage function represents an attractive strategy to ameliorate disease. The aim of the current proposal is to dissect the role of the macrophage in the pathophysiology of diabetic kidney disease and to attempt to retard progression of nephropathy by manipulating macrophage function.

First, I will use an incisive conditional macrophage ablation strategy to induce selective macrophage depletion in a model of type 1 diabetes. These experiments will delineate the specific role of macrophages in the pathogenesis of diabetic nephropathy. I will then harness the predilection of macrophages to localise to inflamed tissues to deliver gene therapy selectively to the kidney. I will attempt to inhibit progression of diabetic nephropathy by administering macrophages that have been genetically modified by adenoviral transduction to over express putative protective factors including (i) heme oxygenase-1, an enzyme with antioxidant properties and (ii) bone morphogenic protein-7, which has previously been demonstrated to inhibit scarring in experimental diabetic nephropathy.

In parallel with these in vivo studies, I will use a variety of in vitro techniques to determine the effect of modified ‘diabetic extracellular matrix‘ which accumulates during disease upon key macrophage functions including macrophage activation, deactivation and phagocytosis of apoptotic cells; critically important processes in regulating the balance between promotion and resolution of inflammation. I envisage that these studies will provide a better understanding of the mechanisms underlying the pro-inflammatory nature of diabetic nephropathy and facilitate identification of novel therapeutic targets to dampen the inflammatory process for therapeutic gain.