Aryl Hydrocarbon Receptor Mechanisms Affecting Chronic Kidney Disease

Abstract

The aryl hydrocarbon receptor (AHR) is a basic helix-loop-helix transcription factor that binds diverse endogenous and xenobiotic ligands, which regulate AHR stability, transcriptional activity, and cell signaling. AHR activity is strongly implicated throughout the course of chronic kidney disease (CKD). Many diverse organic molecules bind and activate AHR and these ligands are reported to either promote glomerular and tubular damage or protect against kidney injury. AHR crosstalk with estrogen, peroxisome proliferator-activated receptor-γ, and NF-κB pathways may contribute to the diversity of AHR responses during the various forms and stages of CKD. The roles of AHR in kidney fibrosis, metabolism and the renin angiotensin system are described to offer insight into CKD pathogenesis and therapies.

Jian-Pi-Yi-Shen Formula Improves Adenine-Induced Chronic Kidney Disease via Regulating Tryptophan Metabolism and Aryl Hydrocarbon Receptor Signaling

“…AHR transactivating activity was higher in patients with pre-dialysis CKD stage IV or V than in patients undergoing dialysis, which may be related to the concentration of uremic toxins ( Kim et al, 2020 ). The mechanisms of AHR affecting CKD are thought to be related to the crosstalk between AHR signal and rennin angiotensin aldosterone system, transforming growth factor-β1 (TGF-β1) pathway, and nuclear factor kappa B (NF-κB) pathway ( Curran and Kopp, 2022 ). Therefore, AHR signaling may be a pharmacological target in CKD ( Mo et al, 2020 ).…”

RAGE pathway activation and function in chronic kidney disease and COVID-19

“…This observation suggests a cell signal cascade involving RAGE-induced ROS. Higher ROS levels increase the activity of angiotensin-converting enzyme (ACE), which cleaves Ang I to Ang II, leading to Ang II-induced TGF-β1 production via AT1R cell signaling ( 1 , 48 ). Thus, AT1R and RAGE signaling may contribute to mesangial cell type I collagen production identified in human sclerotic glomerular lesions ( 49 ).…”

“…COVID-19 patients manifest increased levels of sRAGE in plasma ( 100 ) and serum ( 101 ). These increases might arise via various processes: ( 1 ) pre-existing conditions (e.g., diabetes, cardiovascular disease, obesity), ( 2 ) as a response to increased epithelial/endothelial damage, and/or ( 3 ) as a result of SARS-CoV-2 activation of proteases which occurs subsequent to SARS-CoV-2 binding to and modulating the activity of ACE2 ( 102 ). The production of serum sRAGE in asymptomatic patients (≥10 ng/mL) with lower numeric age (average age 43 y) compared to sRAGE levels (<10 ng/mL) in symptomatic elderly patients (average age 62 y) ( 103 ) may suggest a protective role of sRAGE.…”

“…Chronic kidney disease (CKD) is caused by both systemic diseases (e.g., diabetes mellitus, systemic lupus erythematosus, systemic vasculitis, malignant hypertension and viral infections, including hepatitis B and HIV) and primary kidney diseases (e.g., podocytopathies, polycystic kidney disease, interstitial nephritis) ( 1 ). CKD also occurs in patients following infection with coronavirus disease 2019 (COVID-19).…”

From Nucleus to Organs: Insights of Aryl Hydrocarbon Receptor Molecular Mechanisms

“…Consequently, there is thus a crosstalk between the NF-κβ and AHR pathways, in such a way AHR activation favors RelA/p65 protein degradation by ubiquitin–proteasome system (UPS) and lysosomes, resulting in decreased levels of proinflammatory cytokines in mouse macrophages [ 88 ]. In fact, such crosstalk between AHR and NF-κβ pathways could contribute to a variety of AHR responses during the different types and stages of chronic kidney disease (CKD) [ 89 ].…”