Role of Indoleamine 2,3-Dioxygenase 1 in CKD-Related Peripheral Artery Disease

Background: CKD is a strong and independent risk factor for adverse limb events in mice and humans with peripheral artery disease (PAD), in large part contributed by kynurenine, a tryptophan-derived uremic toxin. Indoleamine 2,3-dioxygenase 1 (IDO1) is a key rate-limiting enzyme in converting tryptophan to kynurenine. We set out to understand the role of IDO1 in the development and progression of CKD via an HLI mouse model. Methods: A group of male and female IDO1 global knockout (gKO) mice were compared with wild-type littermates, and a hind limb ischemia model was created following their exposure to a normal chow diet or a 0.2% adenine diet (a CKD model) for six weeks. Mice underwent laser doppler and treadmill training for endurance assays. The ischemic soleus muscles were assayed using CD31 as a marker of endothelial cells and quantitated as integrated density normalized to the surface area. Student’s tests and ANOVA were applied. Results: Compared to wild-type male CKD mice, IDO1 gKO CKD mice showed an 85% increase in hindlimb perfusion at the end of the experiment (P= 0.0438). Global IDO1 KO CKD mice showed a 30% increase in post-exercise hyperemia (P = 0.0386) and a 4-fold increase in the time to exhaustion (P= 0.0345) compared to wild-type CKD mice. Female IDO1 gKO CKD mice showed a 2.8-fold increase in perfusion and a 28% increase in post-exercise hyperemia (P = 0.0096) compared to their control CKD mice (P= 0.0112). The ischemic soleus muscles of both male and female IDO1 gKO mice showed a ~ 2-3-fold increase in the normalized integrated density of CD31 compared to their respective controls (P < 0.0001). No significant differences were noted in the non-CKD male and female groups between controls and IDO1 gKO mice. Conclusion: This study demonstrates that IDO1 regulates post-ischemic angiogenesis and functional performance, specifically in CKD mice with PAD. More work is needed to probe the mechanisms by which IDO1 regulates the PAD phenotype in the CKD milieu. Funding: NIDDK Support