Inhibition of the aryl hydrocarbon receptor decreases T cell populations in Chronic Kidney Disease in male Sprague Dawley rats

Chronic Kidney Disease (CKD) affects 45% of the U.S. population over 70 years old and is the 10 th leading cause of death in the U.S. The tryptophan metabolite, kynurenine has been associated with increased severity of CKD in humans and is a ligand for the aryl hydrocarbon receptor (AhR). CKD is associated with activation of the immune system and increased inflammation. We hypothesized that kynurenine in CKD activates pro-inflammatory T cells via the AhR that amplify disease. We instrumented male and female Sprague Dawley rats with telemeters (n=6 rats/group) and fed a 0.25% adenine diet for 10 weeks. We found that mean arterial pressure increased only in the male rats with CKD (107.3 ± 2.0 to 136.8 ± 12.7 mmHg). Water consumption (28 ± 1 to 69 ± 4 males and 38 ± 2 to 55 ± 5 ml/day females) and urine volume (20 ± 3 to 60 ± 3 ml/day males and 27 ± 2 to 46 ± 4 ml/day females) increased in CKD rats from week 2 though week 8. Glomerular filtration rate was significantly decreased in CKD females after 2 weeks (0.447 ± 0.08 CKD vs. 0.685 ± 0.04 CTL ml/min/100 g BW) and in both sexes after 10 weeks (0.290 ± 0.05 CKD vs. 0.584 ± 0.03 CTL males and 0.331 ± 0.05 CKD vs. 0.685 ± 0.12 CTL females). Renal hypertrophy was evident with CKD in the left kidney in both sexes (2.31 ± 0.08 vs. 1.26 ± 0.04 CTL males and 1.60 ± 0.13 vs. 0.86 ± 0.02 g CTL females) but not in the right (1.40 ± 0.11 vs. 1.27 ± 0.03 CTL males and 0.96 ± 0.06 vs.0.84 ± 0.03 g CTL females). We then instrumented male and female rats with telemeters and catheters for infusion (n=3 rats/group). For the first week, rats were fed the adenine diet with vehicle infusion and then rats received an AhR inhibitor (CH223191, 10 mg/kg) or vehicle with the diet for an additional 3 weeks. At sacrifice, kidneys were harvested for flow cytometric analysis. We found that there were sex differences in immune cell profiles in CKD vehicle-treated rats. Male rats expressed more CD45+, CD3+, CD4+ and CD8+ cells than female rats. AhR inhibition decreased CD45+, CD3+ and CD4+ expression in male CKD rats. A similar trend was evident in female CKD rats. CKD did not significantly alter CD8+ expression in male or female rats. These studies suggest that the AhR may be a reasonable drug target to reduce chronic inflammation and improve GFR in patients suffering with CKD. This work was supported by Career Development Award, IK2BX004997 from the US Department of Veterans Affairs, Biomedical Laboratory Research and Development Service to DLI. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.