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.