Role and Mechanism of PCK2 in Regulating Fatty Acid Oxidation during Kidney Interstitial Fibrosis

Background: Renal interstitial fibrosis is the final stage of the progression of chronic kidney disease. Currently, the means to restore or prevent the renal fibrosis process are still very limited. Abnormal metabolism is an important concomitant feature of renal fibrosis, in which the sharp reduction of fatty acid oxidation capacity is the key factor of tubulointerstitial energy metabolism failure. Phosphoenolpyruvate carboxyl kinase 2 (PCK2) is a mitochondrial subtype of phosphoenolpyruvate carboxyl kinase (PEPCK), widely involved in cell metabolism and plays an important role in maintaining cell homeostasis. However, the role and mechanism of PCK2 in renal interstitial fibrosis have not yet been revealed. Methods: Western blot, immunoblot analysis and immunohistochemistry were used to detect the expression of PCK2. PCK2 over expression lentivirus in HK2 cells and proximal tubule-specific transgenic mice were used to upregulate PCK2. EMT related markers, collagen I, fibronectin, and Hippo signal pathway related makers were detected by western blot and immunofluorescence. Lipid metabolism-related product kits such as triglyceride kits, fatty acid kits, fatty acid synthase kits, and cholesterol detection kits were applied to measure the specific content changes of various lipid components. Results: PCK2 expression is significantly decreased in renal interstitial fibrosis and is highly correlated with the severity of fibrosis. Overexpression of PCK2 can reduce renal interstitial fibrosis. Further research reveals that PCK2 is enriched with multiple lipid metabolism pathways. PCK2 increases the level of renal tubular fatty acid oxidation and activate the Hippo pathway. Conclusion: PCK2/Hippo axis is involved in the progression of renal interstitial fibrosis by regulating fatty acid oxidation. Funding: Government Support – Non-U.S.Schematic diagram