Mechanisms Underlying the Susceptibility and Severity of Acute Kidney Injury

项目总结 急性肾损伤(AKI)仍然是世界范围内的一个严重的健康问题。需要肾脏置换的AKI患者 治疗(透析)仍有50%-60%的死亡率。患者在透析中存活-需要AKI的患者的28倍 发展为慢性肾脏疾病(CKD)的风险增加，导致终末期肾脏疾病 (ESRD)。人们认识到，功能性肾单位对肾单位缺陷的反应是通过增加大小和质量来实现的，但 不是在数量上。这种生长反应称为代偿性肾单位肥大(CNH)，可发生在 人类的许多情况(例如，由于肾损伤、肿瘤、先天性单侧肾脏而进行的外科肾脏消融 发育不全，或捐赠肾脏)。尽管肾脏捐赠者是从健康的人中高度挑选出来的，但最近 研究更新了我们的知识，越来越多的文献表明，肾脏捐赠者确实有更高的风险 发展CKD和ESRD。我们的目标是确定CNH以前未明确的致病作用 急性肾损伤的易感性和严重性以及在加速间质纤维化发展中的作用 在对抗AKI和CKD方面。我们还将研究肥大的肾单位通过其分子机制 对急性和慢性损伤敏感，长期目标是确定分子靶点以减少发病率 AKI和CKD的发展和/或进展为ESRD。我们的中心假设是CNH使 肾单位损伤并启动肾单位丢失的循环肾单位肥大，从而耗尽功能 肾素加速，最终导致终末期肾病。我们的预期结果包括：1)修订后的 对传统所谓“代偿性肾肥大”的认识 肾单位细胞对损伤敏感；2)肾单位缺失肾单位肥大恶性循环的识别 作为一种以前被低估的基本机制，导致进行性肾单位损害；以及3) 寻找新的潜在靶点来脱敏来自缺血性急性肾损伤的肥大肾单位。这个 我们研究的影响将包括：1)建立肾单位丢失肾单位肥大的恶性循环 许多肾脏疾病进行性疾病的重要机制，并记录了 CNH在使肾脏对损伤敏感方面的有害方面；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害的分子机制。这个项目可能 通过靶向特定的信号分子减缓甚至停止，从而导致新的和改进的治疗方法的发展 肾单位丢失的恶性循环肾单位肥大可防止肾脏疾病的进展。目标1将定义 代偿性肾单位肥大在判断急性肾损伤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AKI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.