Tubuloglomerular feedback response in AKI to CKD transition

急性肾损伤(AKI)与发展为慢性肾脏疾病(CKD)的高风险相关，这是 一个日益严重的健康问题困扰着3700万美国成年人，每年花费超过800亿美元。然而， AKI患者发展为CKD的潜在机制，特别是风险因素 还没有完全阐明。另外 ，在预防AKI向CKD转变方面还没有特效的治疗方法。 因此，进一步了解其病理生理机制对于鉴定新的新发病原菌至关重要。 预防AKI向CKD转变的治疗目标。 肾小球滤过率降低是AKI和CKD的一个标志。转化生长因子反应是调控的重要机制之一 GFR。NOS1β是主要的剪接变异体，是致密黄斑产生NO的主要来源。 最近，我们实验室的几项研究证实了致密黄斑nos1β调节的决定性作用。 长期控制肾小球滤过率、钠排泄量和血压的转化生长因子反应。然而，无论是 致密斑型β调节的转化生长因子反应性在急性脑梗塞向慢性肾功能不全转变过程中的重要作用 未知。 在目前的方案中，我们建议检验我们的中心假设，即在肾脏缺血再灌注后，NOS1β的表达 致密黄斑的活性降低，这增强了转化生长因子的反应性，降低了GFR， 从而促进向CKD的过渡。抢救致密黄斑可阻止AKI向CKD的转变。

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.