Abstract: FR-PO0296
High Glucose- and Adenine-Induced Endothelial Dysfunction Involves Activation of the cGAS-STING Signaling Pathway and Suppression of Endothelial Nitric Oxide Synthase (eNOS)
Session Information
- Diabetic Kidney Disease: Basic and Translational Science Advances - 1
November 07, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 701 Diabetic Kidney Disease: Basic
Authors
- Das, Falguni, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
- Tamayo, Ian M., The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
- Lee, Hak Joo, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
- Maity, Soumya, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
- Acosta, Francisca M, 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
Hyperglycemia is a key contributor to endothelial dysfunction, a critical early event in the pathogenesis diabetic complications. However, the molecular mechanisms underlying this dysfunction are not fully understood. Uncovering these pathways may identify novel therapeutic targets, particularly for diabetic kidney disease (DKD).
Methods
In vitro studies utilized Human umbilical vein endothelial cells (HUVECs) and murine microvascular fragments, while in vivo studies employed STZ-induced diabetic rats and OVE26 mice. Methods included immunoblotting, immunoprecipitation, siRNA and plasmid transfections, nitrite assays, and hypertrophy assessment.
Results
HUVECs exposed to 25 mM high glucose (HG) or 20 µM adenine showed hallmark features of endothelial dysfunction, including reduced eNOS expression and nitric oxide (NO) production. High glucose induced time-dependent activation of mTORC1 and mTORC2, evidenced by increased phosphorylation of S6K and Akt (Ser-473) respectively. PI3K inhibition (LY294002) and Akt inhibition (MK-2206) suppressed these phosphorylation events and significantly reduced HG-induced hypertrophy and matrix protein accumulation. Similar results were observed with adenine treatment. Both HG and adenine upregulated cGAS and STING, promoting type I interferon and pro-inflammatory cytokine expression, linking metabolic stress to innate immune activation. Modulation of mTORC1 activity via rapamycin or constitutively active mTORC1 expression confirmed mTOR-dependent regulation of cGAS–STING signaling. Notably, knockdown of cGAS, as well as rapamycin treatment, restored eNOS expression and NO levels. Furthermore, MTDIA, a methylthioadenosine phosphorylase (MTAP) inhibitor, reversed HG-and adenine-induced eNOS suppression and mitigated HG-induced aberrant microvascular sprouting in culture. In vivo relevance was confirmed in the renal cortex of STZ rats and Ove 26 mice. In both models we found decreased expression of eNOS alongside increased pS6K, pAkt, cGAS, STING, fibronectin, and collagen I (α2) levels.
Conclusion
These findings suggest that hyperglycemia-induced endothelial dysfunction is mediated via the HG-MTAP-adenine-PI3K–Akt–mTOR–cGAS–STING axis. Targeting this pathway may offer therapeutic benefit in preventing or reversing endothelial dysfunction in DKD.
Funding
- Veterans Affairs Support