Abstract: SA-PO0036
Human Kidney Organoids Reveal MTAP-Adenine Axis as a Driver of Cyst Growth in ADPKD
Session Information
- Development, Stem Cells, and Regenerative Medicine
October 24, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Development, Stem Cells, and Regenerative Medicine
- 700 Development, Stem Cells, and Regenerative Medicine
Authors
- Das, Falguni, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
- Schreiber, Megan, University of Southern California Keck School of Medicine, Los Angeles, California, United States
- Li, Zhongwei, University of Southern California Keck School of Medicine, Los Angeles, California, United States
- Sharma, Kumar, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
Background
Autosomal dominant polycystic kidney disease (ADPKD) is a progressive cystic disorder with limited therapies. Dysregulated purine metabolism contributes to disease progression, but mechanisms remain unclear. We investigated the role and therapeutic potential of the methylthioadenosine phosphorylase (MTAP)-adenine axis in ADPKD cystogenesis using human kidney organoids.
Methods
Studies were performed in human proximal tubular epithelial (HK-2) cells and human pluripotent stem cell-derived kidney organoids, including PKD2 knockout (PKD2KO) and wild-type controls. Analyses included immunofluorescence, viability assays, metabolomics, immunoblotting, phase-contrast imaging, and cellular hypertrophy. Gene manipulation was performed by transient transfection. Statistical analyses were conducted using GraphPad Prism
Results
mTOR signaling is implicated in ADPKD. HK-2 cells exposed to high glucose (HG, 25 mM) or adenine (20 µM) showed mTOR hyperactivation, evidenced by increased phosphorylation of S6K and Akt. Both conditions increased extracellular matrix (ECM) protein expression (fibronectin and collagen Iα2), a key feature of cyst expansion and fibrosis, and induced cellular hypertrophy. These effects were attenuated by rapamycin, which reduced ECM protein expression and cellular hypertrophy. As rapamycin and its analogs show potential in PKD, but limited by side effects and partial efficacy, we targeted the MTAP-adenine axis using small molecule transition-state inhibitors of MTAP. The MTAP inhibitor reduced mTOR activation and ECM protein expression and attenuated cellular hypertrophy under HG conditions. Consistently, MTAP knockdown by siRNA produced similar effects, supporting a central role of this pathway in PKD pathology. In human PKD2KO organoids, marked cyst formation and increased organoid size were observed compared to wild-type controls, along with an elevated adenine-to-methylthioadenosine (MTA) ratio. MTAP inhibition reduced this ratio and was associated with decreased cyst formation and organoid size.
Conclusion
Our findings show a novel metabolic mechanism in which dysregulation of the MTAP-adenine axis drives metabolic reprogramming and cystogenesis in ADPKD organoids. Targeting MTAP restores purine balance and attenuates cyst formation in PKD2-deficient models, supporting kidney organoids as a platform for therapeutic discovery and MTAP as a therapeutic metabolic target upstream of mTOR.
Funding
- Veterans Affairs Support