Role of JNK and p38 MAPK signalling in diabetic nephropathy

JNK 和 p38 MAPK 信号在糖尿病肾病中的作用

• 批准号: nhmrc : 338517
• 负责人: A/Pr David Nikolic-Paterson
• 金额: $ 30.31万
• 依托单位: Prince Henry's Institute of Medical Research
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2005
• 资助国家: 澳大利亚
• 起止时间: 2005-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/role-jnk-p38-diabetic-nephropathy/95303
• 关键词: Role; JNK; p38; MAPK; signalling

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.

肾衰竭是我们社区的一个主要健康问题。进展为终末期肾衰竭的患者依赖于终生透析或移植（一种昂贵且复杂的治疗）。过去十年，患终末期肾衰竭的患者数量急剧增加，这主要是由于糖尿病肾病发病率的增加。事实上，最近的 AusDiab 全国调查发现，高达 25% 的澳大利亚成年人口患有糖尿病或葡萄糖不耐症（糖尿病的前兆）。大约 50% 的糖尿病患者会患上肾脏疾病，尽管最近在更好地控制血糖和血压方面取得了进展，但大多数糖尿病患者的肾脏疾病将不可避免地发展为终末期肾衰竭。因此，迫切需要改进糖尿病患者的治疗策略，以避免肾衰竭。我们已经鉴定出细胞内的一组蛋白质（称为 JNK 和 p38 的酶）在非糖尿病肾病的发展中发挥因果作用。最近，我们发现这些蛋白质（JNK 和 p38）活性的增加与人类和实验性糖尿病肾病的发生有关。因此，该项目将使用两种互补的方法（药物和转基因小鼠）阻断 JNK 和 p38 的作用，以确定靶向这些蛋白质是否可以抑制糖尿病肾病的发展。此外，有证据表明，阻断这些蛋白质可能对 2 型糖尿病患者的胰岛素抵抗和血糖升高产生有益影响。如果这些假设得到证实，这将为糖尿病肾病甚至糖尿病本身的治疗提供明确的治疗目标。此外，由于这些蛋白质的抑制剂已经进入其他适应症的临床试验，因此针对糖尿病肾病的这一机制是一个现实的目标。