ASN's Mission

To create a world without kidney diseases, the ASN Alliance for Kidney Health elevates care by educating and informing, driving breakthroughs and innovation, and advocating for policies that create transformative changes in kidney medicine throughout the world.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on X

Kidney Week

Abstract: FR-PO375

Inhibition of Endogenous Adenine Synthesis Ameliorates Kidney Injury in db/db Mice with Type 2 Diabetes

Session Information

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