As the increasing burden of chronic kidney disease (CKD), acute kidney injury (AKI) is recently recognized playing an important role of it. Growing evidence suggests AKI is associated with the subsequent development of CKD, even without preexisting kidney disease. Hence for patients with de novo AKI, prevention for ensuing CKD and treatment of whole AKI-CKD continuum are important. Although the precise mechanisms liking AKI to CKD remain unclear, recent studies reveal that AKI-related mitochondria dysfunction plays a key role of AKI-CKD development. In this project, we will apply cisplatin (CP) and hypoxia (ischemia/reperfusion) injury respectively to establish AKI-induced CKD models in vitro and in vivo. CP-induced AKI is a well-studied model of nephrotoxicity in rodents. A robust mouse model with unilateral ischemia-reperfusion (IR) was also suggested to study the progression from acute renal injury to long term tubulo-interstitial fibrosis. CP rapidly accumulates in mitochondria and deteriorates the mitochondrial structure and metabolic function. Mitochondrial oxidative damage is a significant contributor to the early phases of IR injury. Recent findings find the mitochondria are also involved in progression of chronic kidney damage. Mitochondria protection after AKI is potential to arrest CKD. Peroxisome proliferator-activated receptor alpha (PPAR) can enhance mitochondrial biogenesis and augment the oxidation of fatty acids. Our previous study shows that PPAR protects renal tubular cells from gentamicin-induced apoptosis. PPAR activation is potential to reduce AKI and mitigate CKD. Beraprost, L-carnitine and coenzyme Q10 are reported to activate PPAR directly or indirectly. Therefore, we hypothesized that 1) some AKI biomarkers are highly correlated to CKD; 2) PPAR activation is potential to prevent and treat acute to chronic kidney injury. In this project, we will investigate the role and molecular mechanism of AKI biomarkers and PPAR activation in AKI-induced CKD models. The specific aims of this project are listed as below: 1. To identify the influence of CP/hypoxia on pressure or TGF--induced fibrotic responses . 2. To identify the influence of beraprost/L-carnitine/coenzyme Q10 on mitochondrial injury-related fibrotic responses. 3. To analyze the correlation between potential markers and mitochondrial injury-related fibrotic responses. 4. To identify the influence of beraprost/L-carnitine/coenzyme Q10 on renal fibrosis in the AKI-to-CKD mouse model. 5. To analyze the correlation between potential AKI markers and CKD progression in the AKI-to-CKD mouse model. This study will identify potential biomarkers and develop therapeutic agents for the prevention and treatment of AKI-CKD continuum.
|Effective start/end date||8/1/17 → 7/31/18|
- acute kidney injury
- chronic kidney disease
- peroxisomeproliferator-activated receptor alpha
- renal tubular cells