Kidney Week

Abstract: TH-PO0244

Indoxyl Sulfate Promotes Uremic Arterial and Venous Thrombosis via SHFM3-Mediated Stabilization of Indoleamine 2,3-Dioxygenase 1

Session Information

• CKD: Mechanisms of Injury and Fibrosis - 1
  October 22, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 2203 CKD (Non-Dialysis): Mechanisms

Authors

• Sethuraman, Kashvi, Boston Medical Center, Boston, Massachusetts, United States

Kashvi Sethuraman, MS

• Almiron, Ricardo, Boston Medical Center, Boston, Massachusetts, United States

Ricardo Almiron, MSc

• Brahim Malloum, Abbas, Boston University, Boston, Massachusetts, United States

Abbas Brahim Malloum, MD

• Sharma, Arjun, Harvard Medical School, Boston, Massachusetts, United States

Arjun Sharma, PhD

• Wu Wong, David Jasen, Boston Medical Center, Boston, Massachusetts, United States

David Jasen Wu Wong, MS

• Piqueras, Maria del Carmen, Boston University, Boston, Massachusetts, United States

Maria del Carmen Piqueras, MSc

• Lotfollahzadeh, Saran, Boston University, Boston, Massachusetts, United States

Saran Lotfollahzadeh, MD, MSc

• Patel, Arjun M., Boston University, Boston, Massachusetts, United States

Arjun M. Patel

• Natrakul, Anna, Boston University, Boston, Massachusetts, United States

Anna Natrakul

• Chowdhury, Farihah, Boston University, Boston, Massachusetts, United States

Farihah Chowdhury, MS

• Jose, Asha, Boston University, Boston, Massachusetts, United States

Asha Jose, PhD

• Shafiq, Mohammad, Northwestern University, Evanston, Illinois, United States

Mohammad Shafiq, MSc, PhD

• Zhao, Youyang, Northwestern University, Evanston, Illinois, United States

Youyang Zhao, PhD

• Rahimi, Nader, Boston University, Boston, Massachusetts, United States

Nader Rahimi

• Ravid, Katya, Boston University, Boston, Massachusetts, United States

Katya Ravid

• Chitalia, Vipul C., Boston University, Boston, Massachusetts, United States

Vipul C. Chitalia, MD, PhD

Background

The uremic milieu of chronic kidney disease (CKD) is characterized by the accumulation of protein-bound uremic toxins, which contribute to thrombosis. Indoxyl sulfate (IS), a bona fide uremic toxin, upregulates indoleamine 2,3-dioxygenase 1 (IDO1), thereby augmenting Kynurenine (Kyn) biogenesis. Both toxins activate tissue factor (TF) and thrombosis. Despite this pathogenic synergy, the mechanisms of IS-mediated IDO1 stabilization remain undefined.

Methods

We employed targeted metabolomics, super-resolution microscopy, and gain-and loss-of-function experiments using nanoparticle-mediated gene delivery in mice to modulate SHFM3 expression. This was followed by carotid artery or inferior vena cava thrombosis assays in IS-specific and adenine-induced CKD models.

Results

Among several F-box-containing E3 ligases, split-hand/foot malformation 3 (SHFM3) downregulates IDO1 in endothelial cells (ECs). SHFM3 constitutively interacts with IDO1, which is partially disrupted by IS-induced nuclear sequestration of SHFM3 at concentrations corresponding to early to advanced CKD. SHFM3 interacts with the N-terminus of IDO1, ubiquitinates and destabilizes it. IS upregulates IDO1 activity, thereby increasing Kyn biogenesis in N-terminus- and SHFM3-dependent manners. In an IS-specific mouse model, EC-specific SHFM3 silencing increased IDO1 and TF and accelerated arterial thrombosis, and these effects were reversed by EC-specific SHFM3 overexpression. CKD mice exhibited 55% higher venous thrombogenicity than controls. EC-specific SHFM3 overexpression significantly reversed these effects in control mice and to a lesser extent in CKD mice. Serum IS levels significantly correlated with the global IDO1 activity and venous clot weights.

Conclusion

SHFM3 functions as an IS-sensitive potent E3 ligase of IDO1, targeting it for degradation, even with partial interaction with IDO1 in the uremic milieu. This work for the first time describes the CKD-induced venous thrombosis model and supports the selective rewiring of uremic toxins in post-translational proteostasis, amplifying IS-mediated arterial and venous thrombosis. Therapeutically modulating this pathway could mitigate arterial and venous thrombosis in IS-rich milieus.

Acknowledgment

This project was funded by the AHA Cardio-Oncology SFRN CAT-HD Center grant 857078 (KR, VCC, SL, AJ, and XY); R01HL166608 (VCC and KR); T32HL125232 (SL); Center of Cross Organ Vascular Pathology and by the Thrombosis and Hemostasis Affinity Research

Funding

• NIDDK Support