Role of JNK and p38 MAPK signalling in diabetic nephropathy

点击翻译按钮获取中文摘要

Renal failure is a major health problem in our community. Patients who progress to end-stage renal failure are dependent upon lifelong dialysis or transplantation (an expensive and complex treatment). The past decade has seen a dramatic increase in the number of patients developing end-stage renal failure, mainly due to increasing rates of diabetic kidney disease. Indeed, the recent AusDiab nationwide survey that identified diabetes or glucose intolerance (a precursor to diabetes) is now present in up to 25% of the adult Australian population. Around 50% of diabetics develop kidney disease and, despite recent advances in better control of blood glucose and blood pressure, kidney disease in most diabetic patients will inexorably progress to end-stage renal failure. Therefore, there is an urgent need to improve treatment strategies in diabetic patients to avoid kidney failure. We have identified a group of proteins (enzymes called JNK and p38) within cells that play a causal role in the development of non-diabetic forms of kidney disease. Most recently, we have shown that an increase in the activity of these proteins (JNK and p38) is associated with the development of human and experimental diabetic kidney disease. Therefore, this project will block the action of JNK and p38 using two complementary approaches (pharmaceutical drugs and genetically modified mice) to determine whether targeting these proteins can suppress the development of diabetic kidney disease. In addition, there is evidence to suggest that blockade of these proteins may have a beneficial impact upon insulin resistance and elevated blood glucose in type 2 diabetes. If these postulates are proven, this will provide a well-defined therapeutic target for the treatment of diabetic kidney disease, and perhaps diabetes itself. Furthermore, since inhibitors of these proteins are already in clinical trials for other indications, targeting this mechanism in diabetic kidney disease is a realistic goal.