Stress-activated protein kinases - a common pathway of progressive kidney disease.

进展为终末期肾功能衰竭的患者需要终生透析或肾移植治疗。此外，肾功能衰竭是心脏病发作的一个强烈和独立的危险因素。肾功能衰竭是我们社会的一个主要健康问题，涉及患者的福利，以及肾脏替代疗法和心脏并发症的巨额经济成本。即使最近在血压控制方面有所改善，我们在阻止进展和疾病缓解方面仍有很长的路要走。目前的治疗方法仍然是基于非特异性抗炎药物，这些药物具有实质性的、剂量限制的副作用。事实上，我们目前的治疗甚至没有针对进行性肾脏疾病的一些关键致病过程，如细胞凋亡和纤维化。因此，确定进展性肾病的共同机制是很重要的。无论最初肾损害的性质如何，进展型肾脏疾病都会表现出炎症、细胞凋亡和纤维化等常见的致病过程，这些过程不可避免地会导致终末期肾功能衰竭。我们实验室和其他实验室最近的研究表明，这三个致病过程通过一种共同的途径发挥作用，称为SAPK(应激激活蛋白激酶)。这一假说将通过在三种不同的肾脏疾病动物模型中阻断SAPK途径来验证，这三种动物模型的特点是这些关键的致病过程(炎症、凋亡、细胞死亡和纤维化)。SAPK通路的阻断将通过药物和利用基因缺陷小鼠的方式实现。如果这一假设得到证实，这将为进行性肾脏疾病的治疗提供一个明确的治疗目标。事实上，由于SAPK途径的抑制剂已经在其他适应症的临床试验中，将这一机制用于进行性肾脏疾病是一个现实的目标。

Patients who progress to end-stage renal failure require treatment by life-long dialysis or kidney transplantation. In addition, renal failure is a strong and independent risk factor for heart attack. Renal failure is a major health problem in our community in terms of patient welfare and the substantial financial cost of renal replacement therapy and cardiac complications. Even with recent improvements in the control of blood pressure, we still have far to go in terms of halting progression and disease remission. Current therapies are still based on non-specific anti-inflammatory drugs which have substantial, dose-limiting side effects. Indeed, our current therapies do not even target the some of the critical pathogenic processes of progressive kidney disease, such as apoptotic cell death and fibrosis. Therefore, it is important to identify common mechanisms of progressive kidney disease. Irrespective of the nature of the initial renal insult, progressive forms of kidney disease show common pathogenic processes of inflammation, apoptotic cell death and fibrosis that inexorably lead to end stage renal failure. Recent studies from our laboratory, and others, suggest that these three pathogenic processes operate via a common pathway called the SAPK (stress-activated protein kinases). This hypothesis will be tested by blocking the SAPK pathway in three different animal models of kidney disease which feature these key pathogenic processes (inflammation, apoptosis cell death and fibrosis). Blockade of the SAPK pathway will be achieved by means of pharmaceutical drugs and using gene deficient mice. If this hypothesis were proven, this would provide a well-defined therapeutic target for the treatment of progressive kidney disease. Indeed, since inhibitors of the SAPK pathway are already in clinical trials for other indications, targeting this mechanism in progressive kidney disease is a realistic goal.