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

进展到终末期肾衰竭的患者需要终身透析或肾移植治疗。此外，肾功能衰竭是心脏病发作的一个强大而独立的危险因素。肾功能衰竭是我们社区的一个主要健康问题，涉及患者福利和肾脏替代治疗和心脏并发症的大量经济成本。即使最近血压控制有所改善，我们在阻止病情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基于非特异性抗炎药物，这些药物具有严重的剂量限制副作用。事实上，我们目前的治疗方法甚至不能针对进行性肾脏疾病的一些关键致病过程，如凋亡细胞死亡和纤维化。因此，确定进展性肾脏疾病的共同机制非常重要。无论最初肾脏损伤的性质如何，肾脏疾病的进展形式都表现出炎症、凋亡细胞死亡和纤维化等共同的致病过程，这些过程不可避免地导致终末期肾衰竭。我们实验室和其他实验室最近的研究表明，这三种致病过程通过一种称为SAPK（应激激活蛋白激酶）的共同途径起作用。这一假设将通过在三种不同的肾脏疾病动物模型中阻断SAPK通路来验证，这些动物模型具有这些关键的致病过程（炎症、细胞凋亡、细胞死亡和纤维化）。通过药物和基因缺陷小鼠来阻断SAPK通路。如果这一假设被证实，这将为治疗进展性肾脏疾病提供一个明确的治疗靶点。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，针对进展性肾脏疾病的这种机制是一个现实的目标。

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.