Abstract: FR-PO0186
Stress-Inducible ICOSL Preserves Metabolic Tissue Homeostasis and Mitigates Metabolic-Renal Axis Injury
Session Information
- Diabetic Kidney Disease: Metabolic, Mitochondrial, and Inflammatory Mechanisms
October 23, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Cardiovascular-Kidney-Metabolic Health
- 601 Cardiovascular-Kidney-Metabolic Health: Basic
Authors
- Zand, MehrAzin, Rush University Medical Center, Chicago, Illinois, United States
- Jimenez Uribe, Alexis P., Rush University Medical Center, Chicago, Illinois, United States
- Cao, Yanxia, Rush University Medical Center, Chicago, Illinois, United States
- Alcantar, Ariana G., Rush University Medical Center, Chicago, Illinois, United States
- Park, Jooman, University of Illinois Chicago, Chicago, Illinois, United States
- Jiang, Yuwei, University of Illinois Chicago, Chicago, Illinois, United States
- Mangos, Steve, Rush University Medical Center, Chicago, Illinois, United States
- Hahm, Eunsil, Rush University Medical Center, Chicago, Illinois, United States
Background
Inducible T cell costimulator ligand (ICOSL) is classically recognized as an immune costimulatory ligand, but our prior work revealed an unexpected role in renal protection. Its stress-inducible expression in non-immune tissues suggests a broader protective function. Here, we tested whether ICOSL preserves metabolic tissue homeostasis and limits metabolic-renal injury.
Methods
Male and female wild-type and ICOSL-deficient mice underwent baseline metabolic phenotyping, including glucose/insulin tolerance testing, serum hormone profiling, adipocyte morphometry, and adipogenic differentiation assays. ICOSL induction was assessed in adipose tissue and pancreatic β-cells under stress. ICOSL function was further tested in streptozotocin (STZ)- and high-fat diet (HFD)-induced metabolic stress models, and ICOSL small peptide therapy was evaluated in BTBR ob/ob diabetic nephropathy mice.
Results
ICOSL-deficient mice exhibited baseline metabolic abnormalities, including glucose intolerance, insulin resistance, increased adiposity, adipocyte hypertrophy, and reduced adipogenic differentiation potential. These abnormalities were more pronounced in males, with hyperinsulinemia and elevated circulating leptin and resistin levels. In wild-type mice, inflammatory stimulation increased ICOSL expression in visceral adipose tissue, while cytokine or STZ exposure induced ICOSL in a mouse pancreatic β-cell line and human islets, supporting a stress-inducible ICOSL mechanism in metabolic tissues. Under STZ-induced diabetogenic stress, ICOSL-deficient mice developed accelerated hyperglycemia with greater β-cell loss, indicating a protective role for ICOSL in β-cells. Under HFD-induced metabolic stress, female ICOSL-deficient mice remained resistant to obesity but developed glucose intolerance, impaired glucose-stimulated insulin secretion, and reduced circulating C-peptide levels, suggesting β-cell dysfunction despite altered adiposity regulation. Finally, in BTBR ob/ob diabetic nephropathy mice, ICOSL small peptide treatment improved both glucose intolerance and kidney dysfunction, supporting the therapeutic potential of ICOSL-based metabolic-renal protection.
Conclusion
ICOSL emerges as a stress-inducible protective checkpoint for the metabolic-renal axis, highlighting ICOSL peptide therapy as a potential strategy for metabolic syndrome-associated kidney injury.
Funding
- NIDDK Support