Tubuloglomerular feedback response in AKI to CKD transition

急性肾损伤（阿基）与发生慢性肾病（CKD）的风险较高相关， 这一日益严重的健康问题困扰着超过3700万美国成年人，每年造成的损失超过800亿美元。但 潜在机制，尤其是导致阿基患者发展为CKD的风险因素 尚未完全阐明。另外 目前，尚无特异性治疗可用于预防阿基向CKD转变。 因此，进一步了解其病理生理机制对于鉴别新的 预防阿基向CKD转变的治疗靶点。 GFR降低是阿基和CKD的标志。TGF-β反应是调节细胞凋亡的重要机制之一， GFR。NOS 1 β是主要的剪接变体，并参与了致密斑的大部分NO生成。 最近，我们实验室的几项研究证明了致密斑NOS 1 β调节的决定性作用。 TGF反应在GFR，钠排泄和血压的长期控制。然而，无论 致密斑NOS 1 β调节的TGF反应性在阿基向CKD的转变中起重要作用， 未知 在目前的建议中，我们建议验证我们的中心假设，即肾脏IRI后，NOS 1 β表达， 和活性降低，从而增强TGF-β反应性并降低GFR， 从而促进向CKD的转变。拯救致密斑NOS 1可防止阿基向CKD转变。

Acute kidney injury (AKI) is associated with higher risk of developing chronic kidney disease (CKD), which is a growing health problem afflicting over 37 million US adults with cost over $80 billion every year. However, the underlying mechanisms, especially the risk factors that contribute to development into CKD for people with AKI has not been fully elucidated. Additionally , no specific therapy is available in prevention of AKI to CKD transition. Therefore, further understanding the pathophysiological mechanisms is essential for identification of new therapeutic targets for prevention of AKI to CKD transition. Decrease in GFR is a hallmark for AKI and CKD. TGF response is one of important mechanisms that regulate GFR. NOS1β is the primary splice variant and contributes to most of the NO generation by the macula densa. Recently, several studies from our laboratory demonstrated the decisive role of macula densa NOS1β-modulated TGF response in the long-term control of GFR, sodium excretion and blood pressure. However, whether the macula densa NOS1β-modulated TGF responsiveness plays a significant role in transition to CKD from AKI is unknown. In the present proposal, we propose to test our central hypothesis that following renal IRI, NOS1β expression and activity in the macula densa are decreased, which enhance TGF responsiveness and decrease GFR, thereby promoting transition to CKD. Rescue of macula densa NOS1 prevents AKI to CKD transition.