Abstract: PUB367
Adenine Stimulates mTORC1 to Increase Matrix Protein Synthesis, Which Is Inhibited by Hydrogen Sulfide in Kidney Proximal Tubular Epithelial Cells
Session Information
Category: CKD (Non-Dialysis)
- 2203 CKD (Non-Dialysis): Mechanisms
Authors
- Lee, Hak Joo, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
- Gao, Jingli, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
- Liu, Li, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
- Ghosh-Choudhury, Goutam, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
- Kasinath, Balakuntalam S., The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
- Sharma, Kumar, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
Group or Team Name
- Center for Precision Medicine
Background
Adenine promotes chronic kidney disease (CKD) and cardiovascular damage in rodent models. However, the underlying mechanism is poorly understood. Hydrogen sulfide (H2S) deficiency is associated with kidney injury seen in aging and CKD which is ameliorated by exogenous H2S supplementation. We hypothesize that adenine induces kidney injury by activating mTORC1 to increase matrix protein synthesis which is ameliorated by H2S.
Methods
We employed mouse kidney proximal tubule epithelial (MCT) cells. LY294002, MK2206 and rapamycin were used as inhibitors of PI3K, Akt and mTORC1, respectively. Sodium hydrosulfide (NaHS) was used as a source of H2S.
Results
Adenine increased S6K phosphorylation, an index of mTORC1 activity, and fibronectin expression in a dose- and time dependent manner. Inhibitors of PI3K, Akt and mTORC1 abolished adenine-induced S6K phosphorylation. mTORC1 inhibitor also ameliorated adenine-induced fibronectin expression. Administration of NaHS inhibited adenine-induced S6K phosphorylation to ameliorate fibronectin accumulation.
Conclusion
Our results indicate that adenine-stimulated mTORC1 is regulated by PI-3K-Akt signaling. PI-3K-Akt-mTORC1 axis mediates adenine-induced matrix protein synthesis which is ameliorated by exogenous H2S administration. Inhibition of mTORC1 by H2S could be used as a therapeutic intervention for adenine-induced CKD.