Blockade of Aryl Hydrocarbon Receptor Ameliorates Functional Insufficiency in 5/6 Nephrectomized Rat Kidneys by Restoring Hydrogen Sulfide Formation.

Abstract

Aims: We previously demonstrated that aryl hydrocarbon receptor (AhR) activation attenuates the cytoprotective effect of hydrogen sulfide (H₂S), leading to indoxyl sulfate (IS)-mediated renal tubular damage. However, it is unclear whether this pathway would be present in an in vivo uremic model. Results: In a rat chronic kidney disease (CKD) model with 5/6 nephrectomized (Nx), we found that poor renal filtration is associated with accumulation of IS and homocysteine (Hcy), an H₂S precursor. Compared with controls, the protein and mRNA levels of H₂S-producing enzymes, including cystathionine β-synthase, cystathionine γ-lyase, and 3-mercaptopyruvate sulfurtransferase, were attenuated in Nx kidneys. Since the transcription factor, specificity protein 1 (Sp1), acts as an upstream regulator of these enzyme expressions, we found that the protein level and activity of Sp1 were significantly decreased in Nx kidneys. Interestingly, employing the blocker of the AhR CH-223191 not only reverses the decrease in H₂S-producing enzymes and Sp1, but it also reverses H₂S reduction in Nx rats. These are associated with the mitigation of plasma Hcy accumulation, renal excretion, perfusion insufficiency, and tubular damage. Moreover, the oxidative stress in Nx kidneys due to increased superoxide formation and decreased glutathione contents was also attenuated by AhR inhibition. Innovation: Our findings highlight the deleterious effect of AhR activation on renal H₂S formation may be due to IS accumulation and underline AhR blockade as a novel therapy for CKD. Conclusion: AhR is detrimental to Sp1 function in vivo, leading to impeding renal H₂S generation and exacerbating oxidative stress during CKD progression. Antioxid. Redox Signal. 00, 000-000.