Acute kidney injury (AKI) is responsible for about 2 million deaths each year worldwide and its incidence is rising. Increasing evidence indicates that patients who survive an episode of AKI will have a significant risk of progression to chronic kidney disease (CKD) and even to end-stage renal disease (ESRD). Although the severity and frequency of AKI are shown to be closely correlated with poor patient prognosis, the mechanisms governing the different courses of long-term outcome after AKI remains poorly understood. We recently found that interstitial fibroblasts play a central role in orchestrating kidney repair or progression to CKD after AKI, depending on the severity of the insults. There is bidirectional crosstalk between the injured tubular cells and interstitial fibroblasts, mediated by sonic hedgehog (Shh) and Wnt/-catenin signaling. Such an epithelial-mesenchymal communication (EMC) dictates fibroblast cell fate and ultimately the course of AKI outcome. Therefore, the central hypothesis of this application is that fibroblast activation, if transient ad self- limiting, is necessary and advantageous for promoting tubular repair and regeneration, whereas sustained fibroblast activation drives AKI to CKD progression. Several lines of investigation are proposed to test this novel hypothesis.
Aim 1 is to investigate the role of transient fibroblast activation in kidney repair and recovery after AKI.
Aim 2 is designed to investigate the role of sustained fibroblast activation in promoting AKI-CKD progression.
Aim 3 is to investigate the role of EMC in promoting renin-angiotensin system activation and CKD progression. The successful completion of these studies will offer novel insights into the importance and significance of interstitial fibroblasts in dictating kidney repair or progression t CKD after AKI. Undoubtedly, the data generated from this application will have wide implications in designing future therapeutic strategies for preventing AKI to CKD progression in patients.
Acute kidney injury (AKI) is responsible for about 2 million deaths each year worldwide, and its incidence is rising. Increasing evidence indicates that patients who survive an episode of AKI will have a significant risk of progression to chronic kidney disease (CKD) and even to end-stage renal disease (ESRD). The studies proposed in this application promises to provide important insights into understanding the patho- mechanism dictating the divergent courses of AKI, and may offer unique opportunities for designing rational strategies for preventing AKI to CKD progression in patients.
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