Abstract: SA-PO836
UCP2-Regulated HIF-1α Stabilization Promotes Reprogramming of Mitochondrial Metabolism and Induces Tubulointerstitial Fibrosis After Ischemic AKI
Session Information
- Molecular Mechanisms of CKD - III
October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 1903 CKD (Non-Dialysis): Mechanisms
Authors
- Zhou, Yang, Second Affiliated Hospital, Nanjing Medical University, Nanjing, China
- Qin, Nan, Nanjing Medical University, Nanjing, JIANGSU , China
- Yang, Junwei, Second Affiliated Hospital, Nanjing Medical University, Nanjing, China
Background
Acute kidney injury (AKI) is a global public health concern associated with hospitalizations and is especially common in critically ill patients. The transition of AKI to consequence chronic kidney disease (CKD) has major clinical significance. Tubular reabsorption is an energy consumption process relies mainly on mitochondrial metabolism, which is regulated by uncoupling protein 2 (UCP2). Whether UCP2 contributes to the progression of AKI-to-CKD is unknown.
Methods
We generated proximal tubular cells specific UCP2 knockout mice. AKI-to-CKD model was induced using ischemia-reperfusion injury (I/R). Mice kidney tissues were harvested six weeks after I/R. Alternations of mitochondrial morphology, metabolic products and critical enzymes that govern fatty acid oxidation and glycolysis were examined. Pimonidazole was used to evaluate hypoxia in kidney tissue.
Results
In I/R-induced AKI-to-CKD model, expression of UCP2 was markedly increased in fibrosis kidneys. Impairment of renal function and remarkable accumulation of extracellular matrix in the tubulointerstitial spaces were quite evident six weeks after I/R injury. Mitochondria reduction and swellings, as well as lipid droplets deposition suggested metabolic abnormalities of fatty acid. However, increased glycolytic enzyme expression and inhibitory phosphorylation of pyruvate dehydrogenase were exhibited indicating a switch to glycolysis. Ucp2-deficient mice suffered I/R injury experienced less tubulointerstitial fibrosis and metabolic disorders. Furthermore, tissue hypoxia was observed in I/R-induced fibrotic kidney and renal expression of hypoxia-inducible factor 1α (HIF-1α) was increased suggested hypoxia-induced stabilization of HIF-1α in fibrosis kidney. Nevertheless, knockout of UCP2 relieves the tissue hypoxia and reduces the stabilization of HIF-1α in the kidney.
Conclusion
UCP2 regulates tissue hypoxia-induced stabilization of HIF-1a, which promotes the reprogramming of mitochondrial metabolism from fatty acid oxidation to glycolysis and contribute to pathogenesis of AKI-to-CKD. UCP2 may provide a novel therapeutic target for prevention of chronic fibrosis caused by AKI.
Funding
- Government Support - Non-U.S.