Abstract: PO2131
Altered Tryptophan Catabolism via the Kynurenine Pathway Associates with CKD-Accelerated Atherosclerosis
Session Information
- Mechanisms of Kidney and Vascular Disease
October 22, 2020 | Location: On-Demand
Abstract Time: 10:00 AM - 12:00 PM
Category: Hypertension and CVD
- 1403 Hypertension and CVD: Mechanisms
Authors
- Cheofor, Vetalise Konje, University of Michigan Medical School, Ann Arbor, Michigan, United States
- Roeser, Nancy F., University of Michigan Medical School, Ann Arbor, Michigan, United States
- Zeng, Lixia, University of Michigan Medical School, Ann Arbor, Michigan, United States
- Byun, Jaeman, University of Michigan Medical School, Ann Arbor, Michigan, United States
- Mathew, Anna Vachaparampil, University of Michigan Medical School, Ann Arbor, Michigan, United States
Background
Non-traditional risk factors like inflammation and oxidative stress play an essential role in the increased cardiovascular disease risk prevalent in chronic kidney disease (CKD). Tryptophan catabolism by the kynurenine pathway (KP) is linked to atherosclerosis and renal function in both clinical studies and experimental models. However, the role of KP in the pathogenesis of CKD accelerated atherosclerosis is unknown.
Methods
9-week old 5/6 nephrectomized (CKD) and sham-operated (CON) LDLr-/- mice were placed on a high-fat/high-cholesterol diet (HFD) for 16 weeks. KP metabolites were measured using targeted mass spectrometry in the plasma, urine, and tissues. Expression and activity of Indoleamine 2,3 dioxygenase (IDO1- first step of the KP) were quantified by immunoblotting, immunohistochemistry, and kynurenine to tryptophan ratio (KTR) in aortic tissue in both groups.
Results
CKD mice demonstrate increased KP metabolites compared to sham-operated mice (CON) both at baseline and after exposure to HFD for 16 weeks. Exposure to HFD for 16 weeks increases most KP metabolites in both CON and CKD mice, except for levels of tryptophan and 3-hydroxy anthranilic acid that decrease with HFD exposure. 3-hydroxy kynurenine and kynurenic acid increase with HFD exposure in CKD mice, whereas these levels tended to decrease in controls. Hepatic tissue in the CKD mice fed HFD reveals no changes in KP metabolites except increased quinolinic acid, whereas the splenic tissue and renal tissue reveals low tryptophan levels and higher KTR, kynurenic acid, and anthranilic acid. These changes in the HFD fed CKD mice are likely due to a combination of increased synthesis in specific tissues and reduced clearance. IDO expression and activity were also increased in atherosclerotic lesions of CKD mice on HFD for 16 weeks compared to control mice with intact renal function.
Conclusion
In summary, KP metabolites are altered both in the circulation, tissues, and arterial wall of the CKD atherosclerosis model implicating KP in the pathogenesis of atherosclerosis in CKD.
Funding
- Other NIH Support