Abstract: TH-PO905
Lactate Induced Interstitial Fibroblasts Activation and Extracellular Matrix Accumulation in Folic Acid Induced AKI
Session Information
- Molecular Mechanisms of CKD - I
October 25, 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
- Jiang, Lei, Second Affliliated Hospital, Nanjing Medical University, Nanjing, China
- Shen, Yan, Nanjing Medical University, Nanjing, JIANGSU , China
- Yang, Junwei, Second Affliliated Hospital, Nanjing Medical University, Nanjing, China
Background
Recent studies have indicated a substantial proportion of acute kidney injury (AKI) patients may undergo chronic kidney disease (CKD) in long term follow-up. However, the mechanisms are still unclear. Previous evidences affirmed that interstitial myofibroblasts play a key role in AKI-CKD transition. In previous tests, we observed folic acid (FA) injection could induce extracellular matrix (ECM) deposition. Further researches revealed tubular epithelial and interstitial cells proliferate after FA-AKI and the later was significantly delayed than the former. Meanwhile, we confirmed there was active glycolysis in proliferative tubular epithelial cells and secreted abundant lactate after FA-AKI injury. Thus, we speculated the glycolysis metabolic end-product lactate secreted by injured renal tubular epithelial cells induced the activation of interstitial fibroblasts and led to ECM accumulation in folic acid AKI models.
Methods
We checked whether lactate itself could induce fibroblasts activation and express fibrotic proteins. In vivo, rat kidney fibroblast (NRK-49F) were exposed to lactate at different concentration and time interval, harvested and subjected to different detection methods. Secondly, different glycolytic inhibitors 2-deoxyglucose (2-DG) and oxamate were explored in FA treatment mice. Lactate production at acute injured phase was measured. We further verified whether ECM deposition was alleviated after suppressing lactate production. Finally, we preliminary explored the possible molecular mechanisms of lactate in the activation of interstitial fibroblasts.
Results
Lactate could induced NRK-49F cells activation and expressed abundant fibrotic proteins such as alpha-smooth muscle actin (α-SMA), fibronectin (FN). Both 2-DG and oxamate could inhibit the production of lactate by renal tubular epithelial cells and alleviated FA-AKI associated ECM deposition. The protective effects improved with the dose increased and 2-DG seemly more excellent. Lactate may stimulate fibroblasts via altering fibroblasts energy metabolism or affecting proliferative associated cells growth factors expression in fibroblasts.
Conclusion
Lactate secreted by injured renal tubular epithelial cells may play a key role in the activation of fibroblasts and ultimately led to abundant ECM accumulation in folic acid induced acute kidney injury.
Funding
- Government Support - Non-U.S.