Abstract: SA-PO324
Indole-3-Methanol, a Dietary Constituent, Suppresses Uremic Toxicity of Indoxyl Sulfate
Session Information
- Hypertension and CVD: Mechanisms
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Hypertension and CVD
- 1403 Hypertension and CVD: Mechanisms
Authors
- Richards, Sean, Boston University Medical Center, Boston, Massachusetts, United States
- Walker, Joshua A., Boston University, Boston, Massachusetts, United States
- Arinze, Nkiruka, Boston Medical Center, Boston, Massachusetts, United States
- Whelan, Stephen A., Boston University, Boston, Massachusetts, United States
- Lee, Norman, Boston University, Boston, Massachusetts, United States
- Brown, Lauren E., Boston University, Boston, Massachusetts, United States
- Chitalia, Vipul C., Boston University School of Medicine, Boston, Massachusetts, United States
Background
Indoxyl sulfate (IS), a bonafide uremic toxin, mediates its vasculotoxicity in chronic kidney disease (CKD) patients through activation of the Aryl hydrocarbon receptor (AHR)-tissue factor (TF) pathway in vessel walls. The management of patients with CKD focuses primarily on therapies to control the comorbidities associated with and contributing to CKD progression and recommends alterations in macronutrients. In essence, the current management of CKD patients completely lacks the strategies to directly target indolic toxins to prevent/retard the cardiovascular complications. The structural features of IS that impart toxicity and their therapeutic implications remain unknown.
Methods
A structure-activity analysis was conducted using an analog-by-catalogue approach, with the AHR-TF-thrombosis axis as a readout. A set of indolic compounds, including IS bioisosteres were analyzed in a three-tiered system along with validation in two human cohorts. This study employed three distinct animal models and two human cohorts to establish the role of the lead analog.
Results
Replacement of the sulfate moiety abrogated IS-mediated AHR-TF activation. Notably, of all the analogs, Indole-3-methanol (a.k.a. indole-3-carbinol or “I3M”) showed a dose-dependent inhibition of the AHR-TF axis and suppressed IS-induced AHR activation and carotid artery thrombosis in discrete animal models. Mechanistically, I3M reduced TF protein without downregulating its mRNA. I3M suppressed TF in cells specifically in sera from CKD patients compared to the non-CKD controls, and the extent of TF suppression correlated with their levels of IS. I3Minhibited TF in vascular smooth muscle cells in response to pre-intervention sera from subjects who had developed post-angioplasty thrombosis from a sub cohort of a Thrombolysis in Myocardial Infarction-II trial.
Conclusion
This study demonstrates the importance of the IS sulfate group, and reveals I3M, as a suppressor of prothrombotic properties of IS. I3M is a naturally occurring phytochemical found in cruciferous vegetables that a rich source of indole-based glucobrassicin. These results can guide future campaigns to develop targeted therapies such as compounds against IS and plant-based diets that can be personalized to the blood IS levels in CKD patients.
Funding
- Other NIH Support