Abstract: TH-PO0279
Isoform-Specific Role of Akt2 in Adenine-Induced mTORC1 Activation and Kidney Injury
Session Information
- Glomerular Diseases: Cell Biology
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Das, Falguni, 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
Background
Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease, with proximal tubular injury playing a central role in disease progression. Although PI3K/Akt signaling is implicated in DKD, the isoform-specific role of Akt remains unclear. We previously identified Akt-2 as the predominant Akt isoform in the kidney cortex and proximal tubular epithelial cells (HK-2). We also demonstrated that adenine metabolism is dysregulated in diabetes, with increased renal adenine levels potentially contributing to DKD. This study investigated the role of Akt2 in adenine-induced renal injury
Methods
HK-2 cells were used for in vitro studies, and streptozotocin (STZ)-induced diabetic rats for in vivo validation. Methods included immunoblotting, immunohistochemistry, transient transfection assays for gene modulation, immunofluorescence analysis, and measurement of cellular hypertrophy. Statistical analyses were performed using GraphPad Prism.
Results
Adenine time-dependently increased Akt2 phosphorylation at Ser474, with concomitant activation of downstream GSK3β.PI3K inhibition (LY294002) and dominant-negative PI3K inhibition significantly suppressed adenine-induced Akt2 activation and mTORC1 signaling, as evidenced by reduced S6K phosphorylation, and similar effects were observed with Akt inhibition (MK2206).Genetic inhibition using a phospho-deficient Akt2 mutant or Akt2 siRNA markedly attenuated adenine-induced mTORC1 signaling (4EBP1/S6K phosphorylation), confirming a central role for Akt2. Functionally, Akt2 inhibition prevented adenine-induced proximal tubular hypertrophy. In vivo, diabetic rats exhibited increased renal cortical Akt2 phosphorylation, associated with elevated extracellular matrix protein expression, including fibronectin. Immunofluorescence analysis further demonstrated increased glomerular Akt2 phosphorylation in diabetic rats compared with controls.
Conclusion
We demonstrate for the first time that adenine activates Akt2 to drive mTORC1 signaling, resulting in proximal tubular hypertrophy and extracellular matrix accumulation. Akt2 serves as a key mechanistic link between adenine metabolism and renal injury in proximal tubular epithelial cells. These findings identify the adenine-Akt2 axis as a novel pathogenic pathway in diabetic kidney disease and highlight Akt2 as a potential therapeutic target for attenuating tubular injury and progressive glomerulosclerosis.
Funding
- Veterans Affairs Support