Tissue and compartment specific based gene expression signatures as new tools to define and predict response to therapeutic renin angiotensin aldosterone system blockage and renal survival in diabetic nephropathy.

慢性肾脏疾病（CKD）现在被认为是一个日益严重的全球公共卫生问题。CKD的不良后果不仅是进展为需要肾脏替代治疗的持续性肾衰竭，而且还增加了心血管并发症的风险。糖尿病肾病（DN）是最致命的糖尿病微血管并发症和终末期肾脏疾病（ESRD）的主要原因在工业化国家。一个主要的主角是肾素血管紧张素醛固酮系统（RAAS）。RAAS激活在DN的病理生物学中具有多方面的驱动作用。RAAS激活，导致肾内血流动力学受损，炎症和纤维化途径激活，从而促进慢性肾内缺氧，进一步导致肾功能进行性恶化。由于现有的治疗方案只能减缓肾功能的逐渐丧失，因此确定新的疾病标志物和分子机制对于识别处于危险中的患者并预防并发症具有重要意义。我们有独特的机会来确定从参与双盲、安慰剂对照的介入试验的早期DN患者中获得的肾活检组织的转录反应。为了实现这一全球目标，我们将结合肾内基因表达谱和高灵敏度的形态计量学分析来发现强大的分子标记，预测肾脏预后和干预反应的变化。此外，肾内基因表达谱与形态计量学和评估的临床数据的相关性使我们能够识别疾病促进因子和保护因子，这是开发先发制人和治疗策略以克服当前限制的关键一步。

Chronic kidney disease (CKD) is now recognized as a growing public health problem of global proportion. The adverse outcome of CKD is not only the progression to persistent renal failure requiring renal replacement therapy, but also the increased risk of cardiovascular complications. Diabetic nephropathy (DN) is the most lethal diabetic microvascular complication and the main cause of end stage renal disease (ESRD) in industrialized countries. A major protagonist is the renin angiotensin aldosterone system (RAAS). RAAS activation has been well established as a multifaceted driver in pathobiology of DN. RAAS activation, leads to impaired intrarenal hemodynamics, activation of inflammatory and fibrogenic pathways, thereby promoting chronic intrarenal hypoxia, which is further causative for progressive deterioration of renal function.Since available therapeutic options only decelerate gradual loss of kidney function, it is of significant importance to define novel disease markers and molecular mechanisms in order to recognize the patients at risk and to prevent complications. We have the unique opportunity to determine the transcriptional response in protocol renal biopsy tissue obtained from patients participating in a double-blind, placebo-controlled interventional trial of RAAS blockade in early DN. To achieve this global goal, we will combine intrarenal gene expression profiles and highly sensitive morphometric analyses to uncover robust molecular markers, which predict renal outcome and change in response to intervention. Moreover, correlation of intrarenal gene expression profiles with morphometric and assessed clinical data enables us to indentify disease promoters and protective factors, which is a crucial step in developing preemptive and therapeutic strategies to overcome current restrictions.