Kidney Week

Abstract: SA-PO770

Bone Marrow Indoleamine 2, 3-Dioxygenase Deficiency Attenuates CKD Associated Atherosclerosis

Session Information

• Hypertension and CVD: Mechanisms
  November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
  Abstract Time: 10:00 AM - 12:00 PM

Category: Hypertension and CVD

• 1503 Hypertension and CVD: Mechanisms

Authors

• Chai, Biaoxin, University of Michigan, Ann Arbor, Michigan, United States

Biaoxin Chai,

• Cheofor, Vetalise Konje, University of Michigan, Ann Arbor, Michigan, United States

Vetalise Konje Cheofor,

• Zeng, Lixia, University of Michigan, Ann Arbor, Michigan, United States

Lixia Zeng,

• Patel, Dheer, University of Michigan, Ann Arbor, Michigan, United States

Dheer Patel,

• Keller, Max, University of Michigan, Ann Arbor, Michigan, United States

Max Keller,

• Roeser, Nancy F., University of Michigan, Ann Arbor, Michigan, United States

Nancy F. Roeser,

• Byun, Jaeman, University of Michigan, Ann Arbor, Michigan, United States

Jaeman Byun,

• Mathew, Anna Vachaparampil, University of Michigan, Ann Arbor, Michigan, United States

Anna Vachaparampil Mathew,

Group or Team Name

• Mathew Lab, University of Michigan

Background

Non-traditional risk factors like inflammation and oxidative stress play an essential role in the increased cardiovascular disease (CVD) risk prevalent in chronic kidney disease (CKD). Indoleamine 2, 3-dioxygenase (IDO1) catabolizes amino acid tryptophan to kynurenine in immune cells and extrahepatic tissues. IDO1 expression and activity are linked to atherosclerosis and renal function in clinical and experimental models. However, the mechanistic link between bone marrow IDO1 expression and CKD accelerated atherosclerosis is unknown.

Methods

Male LDLr^-/- mice underwent sham surgery or 5/6 nephrectomy (CKD) and were placed on a high-fat/high-cholesterol diet (HFD) for 16 weeks. Tryptophan and kynurenine levels were measured using targeted mass spectrometry in the plasma, urine, and tissues. We designed a metabolic flux study using intraperitoneal injection of ¹³C₁₁ tryptophan to delineate the contribution of decreased renal excretion vs. increased production in specific tissues in CKD mice. We then created a chimeric 5/6 nephrectomized male LDLr^-/- mice with bone marrow from control and Ido1^-/- mice, respectively, to demonstrate the role of IDO1 in CKD atherosclerosis. We quantified atherosclerosis with Oil Red-O staining of en face aortic sections. We measured changes in macrophage apoptosis, phagocytosis, and cytokine profiles with IDO1 deficiency.

Results

CKD mice demonstrate lower circulating tryptophan and increased kynurenine to tryptophan ratio (KTR, marker of IDO activity) at baseline and the end of diet than controls. CKD mice demonstrate increased IDO expression and activity in aortic tissue and bone marrow cells. The metabolic flux study revealed that the CKD mice had increased label in kynurenine pools of vascular and bone marrow tissues confirming increased IDO1 activity in these tissues. IDO1 deficiency in the bone marrow of male CKD LDLr^-/- mice decreases atherosclerosis compared to CKD mice with intact bone marrow IDO1 expression. Activated human macrophage cultures reveal that IDO1 depletion increases macrophage apoptosis and decreases phagocytosis and cytokines.

Conclusion

In summary, IDO1 depletion in the bone marrow of CKD mice decreased atherosclerosis by its action on macrophage apoptosis, phagocytosis, and cytokine profiles.

Funding

• Other NIH Support