Mechanisms Underlying the Susceptibility and Severity of Acute Kidney Injury

项目摘要 急性肾损伤（阿基）仍然是全球范围内的严重健康问题。需要肾脏替代的阿基患者 治疗（透析）仍然有50-60%的死亡率。需要透析的阿基患者存活率为28倍， 发生进展性慢性肾病（CKD）的风险增加，导致终末期肾病 （ESRD）。已经认识到，功能性肾单位对肾单位缺陷的反应是体积和质量的增加， 而不是数量。这种生长反应被称为代偿性肾单位肥大（CNH），它可以发生在 在人类的许多情况下（例如，由于肾创伤、肿瘤、先天性单侧肾 不发育，或捐赠肾脏）。虽然肾脏捐赠者是从健康个体中高度挑选出来的，但最近 研究更新了我们的知识，越来越多的记录表明，肾脏捐赠者确实有增加的风险， 发展CKD和ESRD。我们的目标是确定CNH在决定 阿基的易感性和严重性，以及介导间质纤维化的加速发展， 与阿基和CKD作斗争。我们还将研究肥大肾单位的分子机制， 对急性和慢性损伤敏感，长期目标是确定分子靶点，以降低发病率 阿基和CKD发展和/或进展为ESRD。我们的中心假设是CNH敏感 肾单位损伤，并启动肾单位损失-肾单位肥大的循环，从而消耗功能性 肾单位加速恶化最终导致终末期肾病我们的预期成果包括：1）修订 通过证明肥大性肾脏病患者的肾功能不全，理解传统上所谓的“代偿性肾脏肥大”， 肾单位细胞对损伤敏感; 2）鉴定肾单位损失-肾单位肥大的恶性循环 作为一个以前未被充分认识的基本机制，驱动进行性肾单位损伤;和3） 鉴定用于使肥大肾单位对缺血性阿基脱敏的其他潜在新靶点。的 本研究的影响将包括：1）建立肾单位丢失-肾单位肥大的恶性循环， 这是许多肾脏疾病进行性的重要机制， CNH在致敏肾单位损伤中的有害方面; 2）提供必要的临床前知识 关于CNH发生和驱动进行性肾单位损伤的分子机制。这个项目可能 通过靶向特定信号分子以减缓或甚至停止 肾单位损失和肾单位肥大的恶性循环，以防止肾脏疾病的进展。目标1将定义 代偿性肾单位肥大在确定阿基易感性和严重程度中的作用。目标2将 确定代偿性肾单位肥大使肾单位对阿基敏感的机制。目标3将 确定CNH加速肾纤维化发展的机制。

PROJECT SUMMARY Acute kidney injury (AKI) remains a critical health problem worldwide. AKI patients requiring renal replacement therapy (dialysis) still have a 50-60% mortality rate. Patients survived dialysis-requiring AKI have a 28-fold increased risk of developing progressive chronic kidney disease (CKD), leading to end stage renal disease (ESRD). It is recognized that functioning nephrons respond to nephron deficits by increases in size and mass but not in number. Such a growth response is called compensatory nephron hypertrophy (CNH), which can occur in many situations in humans (e.g. surgical renal ablation due to renal trauma, tumor, congenital unilateral renal agenesis, or donating a kidney). Although kidney donors are highly selected from healthy individuals, recent studies have renewed our knowledge by increasingly documenting that kidney donors do have an increased risk of developing CKD and ESRD. Our goal is to define a previously undefined pathogenic role of CNH in determining the susceptibility and severity of AKI and in mediating accelerated development of interstitial fibrosis, a critical area in fighting AKI and CKD. We will also investigate the molecular mechanisms by which hypertrophied nephrons are sensitized to acute and chronic injury, with the long-term goal to identify molecular targets to reduce the incidence of AKI and development and/or progression of CKD to ESRD. Our central hypothesis is that CNH sensitizes nephrons to injury and initiates a cycle of nephron loss  nephron hypertrophy, consequently depleting functional nephrons at an accelerated rate, ultimately leading to ESRD. Our expected outcomes include: 1) a revised understanding of the traditionally so-called “compensatory renal hypertrophy” by demonstrating that hypertrophied nephron cells are sensitized to injury; 2) identification of the vicious cycle of nephron loss  nephron hypertrophy as a previously under-appreciated fundamental mechanism that drives progressive nephron damage; and 3) identification of additional potential new targets for desensitizing hypertrophied nephrons from ischemic AKI. The impact of our study will include: 1) establishment of the vicious cycle of nephron loss  nephron hypertrophy as an important mechanism underlying the progressive nature of many kidney diseases and documenting a deleterious aspect of CNH in sensitizing nephrons to injury; and 2) providing necessary preclinical knowledge about the molecular mechanisms by which CNH occurs and drives progressive nephron damage. This project may lead to development of novel and improved treatment by targeting specific signaling molecules to slow or even stop the vicious cycle of nephron loss  nephron hypertrophy to prevent kidney disease progression. Aim 1 will define the role of compensatory nephron hypertrophy in determining susceptibility and severity of AKI. Aim 2 will determine the mechanisms by which compensatory nephron hypertrophy sensitizes nephrons to AKI. Aim 3 will determine the mechanisms by which CNH accelerates development of renal fibrosis.