TABLE 1.
Function of select AHR ligands in chronic kidney disease.
| Molecular class | AHR ligand | Experimental results | Setting | Effect on CKD |
|---|---|---|---|---|
| Non-steroidal anti-inflammatory drug (NSAID) | Diclofenac | Decreased renal perfusion in healthy subjects 1 h after a single oral dose (50 mg) in health subjects | Human | Promotes |
| Anti-inflammatory Bass et al. (2009) | Hellms et al. (2019) | |||
| NSAID | Sulindac | Promotes chronic decrements in glomerular filtration rate in patients with renal insufficiency Murray et al. (1995) | Human | Promotes |
| Anti-inflammatory Ciolino et al. (2006) | ||||
| Quinoline-3-carboxamide derivative that is structurally similar to kynurenine | Laquinimod | Oral therapy (1–25 mg, x3/week) delays the development of lupus nephritis in a murine model Lourenco et al. (2014) | Mouse | Inhibits |
| Anti-inflammatory Blocks S100A9 binding to toll-like receptor (TLR)-4 or receptor for advanced glycation end-products (RAGE) Boros and Vecsei (2020) | ||||
| Quinoline-3-carboxamide derivative that is structurally similar to kynurenine | Paquinimod | Paquinimod in drinking water inhibits glomeruli complement deposition and hematuria in a murine model (Bengtsson et al., 2012) | Mouse | Inhibits |
| Anti-inflammatory Blocks S100A9 binding to TLR4 or RAGE Boros and Vecsei (2020) | ||||
| Quinoline derivative that reversibly inhibits ATP binding to vascular endothelial growth factor receptor-2 (VEGR-2) | Semaxanib | Intravenous (x2/week, 145 mg/m2) administration induced complete resolution of all metastatic tumors in a renal cell carcinoma patient (Jennens et al., 2004) | Human | Inhibits |
| Anti-inflammatory VEGFR-2 inhibitor Mezrich et al. (2012) | ||||
| 4-amino-5-(4-chlorophenyl)-7-(dimethylethyl) pyrazolo [3,4-d]pyrimidine (PP2)] | PP2 | Intraperitoneal (2 mg/kg) injection improves kidney function and attenuates kidney tubular injury in a murine LPS-induced acute kidney injury model Pak et al. (2020) | Mouse | Inhibits |
| Antagonizes proliferation, inflammation, differentiation, adhesion, migration, apoptosis, autophagy and angiogenesis Src family kinase inhibitor Frauenstein et al. (2015) | ||||
| Proton pump inhibitor | Omeprazole | Promotes dose-dependent cell death in human and murine proximal tubular cell lines and in human primary proximal tubular cell cultures (Fontecha-Barriuso et al., 2020) | Human cell culture | Promotes |
| Inhibits parietal cell H+/K + ATP pump Novotna et al. (2014) | ||||
| Proton pump inhibitor | Lansoprazole | Intraperitoneal (25 mg/kg) injection increases cell death and inflammation in a murine cisplatin-induced acute kidney model Ye et al. (2021) | Mouse | Promotes |
| Inhibits parietal cell H+/K + ATP pump Novotna et al. (2014) | ||||
| Antibiotic | Rifampicin | Acute kidney injury in 25 tuberculosis and leprosy patients in response to rifampicin therapy Muthukumar et al. (2002) | Human | Promotes |
| Binds and inhibits bacterial DNA-dependent RNA polymerase Puyskens et al. (2020) | ||||
| Tryptophan metabolite | Kynurenine | Lower estimated glomerular filtration rate was related to higher plasma kynurenine levels in a meta-analysis Cheng et al. (2020) | Human | Promotes |
| Anti-inflammatory Mezrich et al. (2010) | ||||
| Tryptophan metabolite | Indole sulfate | Induces glomerular lesions in mice, alters podocyte function and increases inflammation Ichii et al. (2014) Levels are associated with increased mortality in hospital-acquired acute kidney injury Wang et al. (2019) | Mouse Human | Promotes |
| Pro-inflammatory | ||||
| Uremic toxin Schroeder et al. (2010) | ||||
| Tryptophan metabolite | Indole-3-acetic acid | Blood levels are increased with chronic kidney disease stage 5D and fell substantially after kidney transplantation Liabeuf et al. (2020) | Human | Promotes |
| Pro-inflammatory | ||||
| Pro-thrombotic | ||||
| Uremic toxin Addi et al. (2019) | ||||
| Tryptophan metabolite | Indoxyl glucuronide | Serum levels are elevated in hemodialysis patients Itoh et al. (2013) | Human | Promotes |
| Hypoxic transcription factor antagonist | ||||
| Uremic toxin Asai et al. (2018) | ||||
| Tryptophan photo-oxidation product | 6-formylindolo (3,2-b) carbazole (FICZ) | Intraperitoneally FICZ administered (100 μg/kg/d for 4 days) to mice with rhabdomyolysis and ischemia/reperfusion-induced acute kidney injury attenuated kidney damage Tao et al. (2021) | Mouse | Inhibits |
| Promotes IL-22 production | ||||
| Regulates Th17 and T regulatory cell development | ||||
| Concentration-dependent activity Rannug and Rannug (2018) | ||||
| Polycyclic aromatic hydrocarbons (PAHs) | Benzo (a) pyrene (B[a]P) | Intraperitoneal injection produces oxidative stress, DNA damage and reduced kidney function Deng et al. (2018) | Mouse | Promotes |
| Carcinogen Shimizu et al. (2000) | ||||
| Pseudomonas aeruginosa bacterial pigments | Phenazines (1-hydroxyphenazine, phenazine-1-carboxylic acid, phenazine-1-carboxamide, pyocyanin) | Pseudomonas aeruginosa urinary tract infections are associated with high mortality in hospitalized patients Lamas Ferreiro et al. (2017) | Human | Promotes |
| Pro-inflammatory | ||||
| Cytotoxic Moura-Alves et al. (2014) | ||||
| Mycobacterium tuberculosis bacterial pigment | Naphthoquinone phthiocol | Interstitial nephritis and acute renal failure occur in response to disseminated infection or a localized genitourinary disease Daher Ede et al. (2013) | Human | Promotes |
| Pro-inflammatory | ||||
| Cytotoxic Moura-Alves et al. (2014) | ||||
| Epstein-Barr virus (EBV) latent protein | EBV nuclear antigen 3 | EBV genome is present in proximal tubule epithelial cells of patients with chronic interstitial nephritis Becker et al. (1999) | Human | N/A |
| Function not significantly explored Kashuba et al. (2006) | ||||
| Bioactive compound found in cruciferous vegetables | Indole-3-carbinol (I3C) | Oral pre-treatment (20 mg/kg/day) improves cisplatin-induced acute nephrotoxicity indices in rats El-Naga and Mahran (2016) | Rat | Inhibits |
| Anti-inflammatory | ||||
| Anti-angiogenic (Popolo et al., 2017) | ||||
| Polyphenolic compound present in grapes | Resveratrol | Oral administration (5 mg/day/100 g) at the initiation of a rat anti-glomerular basement membrane nephritis model reduces proteinuria, hypoalbuminemia and hyperlipidemia Nihei et al. (2001) | Rat | Inhibits |
| Antagonizes AHR transcriptional responses in an estrogen receptor-α-dependent manner | ||||
| Chemoprotective | ||||
| Cardioprotective Perdew et al. (2010) |
Legend. Shown are 12 classes of compounds that bind aryl hydrocarbon receptors (AHR), either activating or suppressing AHR activity. Some compounds affect kidney function. Compounds with negative effects tend to speed chronic kidney disease (CKD) progression, while those with positive effects tend to slow CKD progression in animal models and/or human patients.