The endothelial TM-PC system regulates tubular senescence and regeneration via p21 in diabetic nephropathy

糖尿病肾病中内皮TM-PC系统通过p21调节肾小管衰老和再生

• 批准号: 317304630
• 负责人: Professor Dr. Berend Isermann
• 金额: --
• 依托单位: Institut für Laboratoriumsmedizin, Klinische Chemie und Molekulare Diagnostik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/317304630?language=en
• 关键词: endothelial; TM; PC; system; regulates

The endothelial TM-PC system regulates tubular senescence and regeneration via p21 in diabetic nephropathyDiabetic nephropathy (dNP) is the leading cause of end stage renal disease in industrialized countries. Tubulointerstitial fibrosis predicts the decline of renal function better then glomerulosclerosis. The pathomechanisms of tubular injury remain, however, largely unknown, hampering the development of new therapeutic approaches. The latter reflects in part the lack of suitable animal models. We developed a mouse model, diabetic mice with reduced levels of the endothelial cell dependent serine protease activated protein C (aPC, a cytoprotective and anticoagulant protease), which develop marked tubulointerstitial fibrosis if diabetic, enabling us to study mechanisms regulating diabetic tubulointerstitial fibrosis. Preliminary work identified increased expression of p21 and increased tubular senescence in these mice. In vitro studies demonstrate that aPC regulates p21 expression and tubular senescence. Tubular p21 expression is epigenetic regulated, thus potentially contributing to the metabolic memory. Importantly, restoring aPC-dependent signalling can reverse these changes, demonstrating that this pathomechanisms is therapeutically amendable. Based on these results we hypothesize that endothelial dysfunction and loss aPC causes sustained p21 expression and tubular senescence, thus impairing the re-generative tubular capacity in dNP. We hypothesize that this will aggravate chronic tubular injury, but also impair tubular repair after an acute renal injury in pre-existing dNP (acute on chronic kidney injury). The aPC-dependent regulation of tubular senescence and hence tubular regeneration would provide a new framework linking endothelial dysfunction and tubular injury and would provide a unifying mechanism underlying the chronic tubular injury as well as the impaired tubular regeneration after acute kidney injury in dNP. To evaluate the proposed mechanism we intend to address the following aims: Aim 1: Delineate the mechanistic interaction of aPC and p21 in controlling tubular cell proliferation and repair in dNP.Aim 2: Define the mechanistic relevance of hyperglycaemia induced and sustained tubular p21 expression for impaired outcome following acute renal injury.Aim 3: Identify the mechanism through which aPC restricts p21 expression.

糖尿病肾病中内皮 TM-PC 系统通过 p21 调节肾小管衰老和再生糖尿病肾病 (dNP) 是工业化国家终末期肾病的主要原因。肾小管间质纤维化比肾小球硬化更能预测肾功能的下降。然而，肾小管损伤的病理机制仍然很大程度上未知，这阻碍了新治疗方法的开发。后者部分反映了缺乏合适的动物模型。我们开发了一种小鼠模型，即内皮细胞依赖性丝氨酸蛋白酶激活蛋白 C（aPC，一种细胞保护和抗凝蛋白酶）水平降低的糖尿病小鼠，如果患有糖尿病，它们会出现明显的肾小管间质纤维化，使我们能够研究调节糖尿病肾小管间质纤维化的机制。初步研究发现这些小鼠中 p21 表达增加，肾小管衰老增加。体外研究表明 aPC 调节 p21 表达和肾小管衰老。管状 p21 表达受表观遗传调节，因此可能有助于代谢记忆。重要的是，恢复 aPC 依赖性信号传导可以逆转这些变化，表明这种病理机制在治疗上是可以修正的。基于这些结果，我们假设内皮功能障碍和 aPC 丢失导致 p21 持续表达和肾小管衰老，从而损害 dNP 的肾小管再生能力。我们假设这会加重慢性肾小管损伤，而且还会损害先前存在的 dNP（急性慢性肾损伤）急性肾损伤后的肾小管修复。肾小管衰老和肾小管再生的aPC依赖性调节将提供一个连接内皮功能障碍和肾小管损伤的新框架，并将提供慢性肾小管损伤以及dNP急性肾损伤后肾小管再生受损的统一机制。为了评估所提出的机制，我们打算实现以下目标： 目标 1：描述 aPC 和 p21 在控制 dNP 中肾小管细胞增殖和修复方面的机制相互作用。目标 2：定义高血糖诱导和持续的肾小管 p21 表达的机制相关性急性肾损伤后的结果受损。目标 3：确定 aPC 限制 p21 表达的机制。