Abstract: FR-PO375
Inhibition of Endogenous Adenine Synthesis Ameliorates Kidney Injury in db/db Mice with Type 2 Diabetes
Session Information
- Diabetic Kidney Disease: Basic - I
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 701 Diabetic Kidney Disease: Basic
Authors
- Lee, Hak Joo, University of Texas Health San Antonio, San Antonio, Texas, United States
- Zhang, Guanshi, University of Texas Health San Antonio, San Antonio, Texas, United States
- Montellano, Richard, University of Texas Health San Antonio, San Antonio, Texas, United States
- Hejazi, Leila, University of Texas Health San Antonio, San Antonio, Texas, United States
- Matta, Shane, University of Texas Health San Antonio, San Antonio, Texas, United States
- Gao, Jingli, University of Texas Health San Antonio, San Antonio, Texas, United States
- Maity, Soumya, University of Texas Health San Antonio, San Antonio, Texas, United States
- Ghosh-Choudhury, Goutam, University of Texas Health San Antonio, San Antonio, Texas, United States
- Kasinath, Balakuntalam S., University of Texas Health San Antonio, San Antonio, Texas, United States
- Sharma, Kumar, University of Texas Health San Antonio, San Antonio, Texas, United States
Group or Team Name
- Center for Precision Medicine.
Background
Elevation of kidney and urine adenine is associated with chronic kidney disease (CKD) including diabetes. Although adenine administration induces CKD in animal models, the effect of endogenous adenine on diabetic kidney disease (DKD) has not been studied. We hypothesize that inhibition of adenine synthesis ameliorates DKD by inhibiting mTORC in mice with type 2 diabetes.
Methods
C57BL6 WT male mice received adenine containing water or control water for 4 weeks. db/db male mice with type 2 diabetes received methylthioadenosine phosphorylase (MTAP) inhibitor or vehicle by drinking water for 8 weeks. Kidney metabolites were measured by ZipChip mass spectrometry. Mouse proximal tubule (MCT) cells were employed for in vitro experiments.
Results
Adenine increased albuminuria, blood urea nitrogen (BUN), kidney hypertrophy, kidney KIM-1 expression, kidney matrix protein accumulation, and kidney mTORC1 activity in WT mice. Adenine stimulated senescence-associated secretory phenotype along with reduction in Klotho expression in the kidney. Rapamycin (a selective inhibitor of mTORC1) inhibited adenine-induced mTORC1 activation and matrix protein accumulation in the MCT cells. MTAP inhibitor decreased kidney adenine content, serum cystatin C, albuminuria, and urine KIM-1 excretion in diabetic db/db mice. MTAP inhibitor decreased diabetic kidney hypertrophy, KIM-1 expression, fibrosis, and mTORC1 activation in the kidney of db/db mice without changes in BUN, body weight, blood glucose level, and intake of food or water. Klotho expression was increased by MTAP inhibitor in the kidney of db/db mice. MTAP inhibitor did not affect other diabetes-related metabolites.
Conclusion
Our data suggest that elevation of adenine drives DKD which is ameliorated by inhibiting adenine synthesis in the kidney. Therefore, adenine metabolism could be used for a biomarker and therapeutic target of DKD.
Funding
- NIDDK Support