摘要：SummaryTissue fibrosis compromises organ function and occurs as a potential long-term outcome in response to acute tissue injuries. Currently, lack of mechanistic understanding prevents effective prevention and treatment of the progression from acute injury to fibrosis. Here, we combined quantitative experimental studies with a mouse kidney injury model and a computational approach to determine how the physiological consequences are determined by the severity of ischemia injury and to identify how to manipulate Wnt signaling to accelerate repair of ischemic tissue damage while minimizing fibrosis. The study reveals that memory of prior injury contributes to fibrosis progression and ischemic preconditioning reduces the risk of death but increases the risk of fibrosis. Furthermore, we validated the prediction that sequential combination therapy of initial treatment with a Wnt agonist followed by treatment with a Wnt antagonist can reduce both the risk of death and fibrosis in response to acute injuries.Graphical AbstractDisplay OmittedHighlights•Quick repair and complete resolution are incompatible requirements for AKI repair•Four discrete terminal states are revealed depending on the duration of ischemia•Imperfective adaptive response state reduces death risk but increases CKD risk•Sequential combination therapy was effective in reducing both death and fibrosisPhysiology; Pathophysiology; Cellular Physiology; Molecular Physiology; Mathematical Biosciences
