Aristolochic Acid-Induced Nephrotoxicity: Molecular Mechanisms and Potential Protective Approaches

Abstract

Aristolochic acid (AA) is a generic term that describes a group of structurally related compounds found in the Aristolochiaceae plants family. These plants have been used for decades to treat various diseases. However, the consumption of products derived from plants containing AA has been associated with the development of nephropathy and carcinoma, mainly the upper urothelial carcinoma (UUC). AA has been identified as the causative agent of these pathologies. Several studies on mechanisms of action of AA nephrotoxicity have been conducted, but the comprehensive mechanisms of AA-induced nephrotoxicity and carcinogenesis have not yet fully been elucidated, and therapeutic measures are therefore limited. This review aimed to summarize the molecular mechanisms underlying AA-induced nephrotoxicity with an emphasis on its enzymatic bioactivation, and to discuss some agents and their modes of action to reduce AA nephrotoxicity. By addressing these two aspects, including mechanisms of action of AA nephrotoxicity and protective approaches against the latter, and especially by covering the whole range of these protective agents, this review provides an overview on AA nephrotoxicity. It also reports new knowledge on mechanisms of AA-mediated nephrotoxicity recently published in the literature and provides suggestions for future studies.

Keywords: DNA adducts formation; aristolochic acid; aristolochic acid nephrotoxicity; potential protective mechanisms; upper urothelial carcinoma.

Figure 1

Formula of the most abundant and active of Aristolochic acids compounds: Aristolochic acid I and Aristolochic acid II.

Figure 2

Proposed metabolic pathway of AAI and AAII which leads to their activation. AAI and AAII are reduced by NAD(P)H: quinone oxidoreductase 1 (NQO1), and cytochrome P450 1A1/1A2 (CYP1A1/2) into N-hydroxyaristolactams, which can further bind to DNA to form AA-DNA adducts, including7-(deoxyadenosin-N6-yl) aristolactam I and II (dA-AAI and dA-AAII), and 7-(deoxyguanosin-N2-yl) aristolactam I and II (dG-AAI and d G-AAII). N-hydroxyaristolactams can also react with sulfotransferases (SULTs) to form N-sulfoxyaristolactam, which can be transformed into aristolactam nitrenium ions? (There is still a matter of debate on the conversion of N-sulfoxyaristolactam into aristolactam nitrenium ions, hence the question mark in Figure 2.) These DNA adducts lead to tumor suppressor Tp53 gene mutations.

Figure 3

Schematic representation of mechanisms of AAI-induced oxidative stress and apoptosis and protective mechanisms. OAT: organic anion transporter; ROS: reactive oxygen species; NAC: N-acetylcysteine; MAPK: mitogen-activated protein kinase; 4-PBA: 4-phenylbutyrate; Bax: Bcl-2-associated X protein; eIF2α: eukaryotic initiation factor-2α; CHOP: CCAAT-enhancer-binding protein homologous protein; XBP1: X-box binding protein 1; OGG1: 8-Oxoguanine glycosylase gene; PARP1: poly [ADP-ribose] polymerase 1 gene; Tp53: tumor suppressor gene; ↑= increase; ↓= decrease; ┴ = inhibition; the thick orange arrows indicate the entry of the toxic compound AAI into the cell; the thick black arrows indicate the exit of endogenous molecules (e.g., glutarate) from the cell. Exposure of proximal tubular cells to AAI, which enter these cells through OAT1/OAT3, increases ROS which can lead to DNA damage (downregulation of DNA repair genes: Tp53, OGG1), endoplasmic reticulum (ER) stress leading to an increase in Ca²⁺, which in turn affect mitochondria that release Cytochrome C (Cyt C). Cyt C activates caspase-3 leading to apoptosis. AAI-induced ER stress increase some of its protein complex (eIF2a, CHOP, GRP78), which can lead to apoptosis. AAI activates MAPK, which in turn activates p38 or p53 leading to apoptosis. AAI can increase NOX2 activity leading to ROS. Probenecid inhibits the entry of AAI through OAT1/OAT3. Antioxidants (vit E, vit C, NAC, GSH) decrease ROS generated by AAI.

Figure 4

Proposed signaling pathway involved in AA-induced inflammatory responses and fibrosis in an animal model. ↑: increase of activation (of receptors); ┬ = inhibition; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; ECM: extracellular matrix; Smad: mothers against decapentaplegic homolog. Exposure to AA activates tumor necrosis factor (TNF) and transforming growth factor beta (TGF-β) which trigger a cascade of reactions leading to activation of proinflammatory and profibrotic genes, then to inflammation and fibrosis, respectively.