Ferroptosis-centered Disease Response Information

General Information of the Disease (ID: DIS00130)
Name
Aristolochic acid nephropathy
ICD
ICD-11: GB55
Full List of Target(s) of This Ferroptosis-centered Disease
Phospholipid hydroperoxide glutathione peroxidase (GPX4)
 Target Info 
In total 2 item(s) under this target
Experiment 1 Reporting the Ferroptosis-centered Disease Response by This Target [1]
Target for Ferroptosis Suppressor
Responsed Disease Aristolochic acid nephropathy [ICD-11: GB55]
Responsed Drug Aristololactam Investigative
 Drug Info 
Responsed Regulator Nuclear receptor subfamily 1 group D member 1 (NR1D1) Driver
 Regulator Info 
Pathway Response Ferroptosis hsa04216
Glutathione metabolism hsa00480
Cell Process Cell ferroptosis
In Vitro Model mRTECs (Mouse renal tubular epithelial cells)
M4100-57 (Mouse renal tubular epithelial cells)
In Vivo Model
Wild-type C57BL/6 mice (eight-week-old, male) were obtained from SPF Biotechnology (Beijing, China). Three sets of animal experiments were performed. In the first set of experiments, male wild-type mice (eight-week-old) were randomly assigned to three groups (n = 6 per group): control group, 2.5 mg/kg AAI group, and 5 mg/kg AAI group. The AAI groups of mice were intraperitoneally injected with AAI (2.5 or 5 mg/kg) once daily for 5 days. The control group of mice were treated with vehicle (corn oil). In the second set of experiments, male Rev-erbfl/fl and Rev-erbkKO mice (eight-week-old) were treated with AAI (5 mg/kg) or vehicle once daily for 5 days by intraperitoneal injection. In the third set of experiments, male wild-type mice (eight-week-old) were randomly divided into the following four groups (n = 6 per group): AAI + SR8278, AAI + DFO, AAI, and vehicle.

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Response regulation Renal REV-ERB protein was significantly increased in aristolochic acid I-treated mice. Furthermore, knockdown of Rev-erb by siRNA or SR8278 (a REV-ERB antagonist) treatment attenuated ALI-induced ferroptosis in mRTECs. SR8278 treatment enhanced the cell survival and GPX4 expression in ALI-treated mRTECs. Taken together, small molecule antagonism of REV-ERB alleviates aristolochic acid I-induced renal injury probably through inhibiting ferroptosis in mice.
Experiment 2 Reporting the Ferroptosis-centered Disease Response by This Target [1]
Target for Ferroptosis Suppressor
Responsed Disease Aristolochic acid nephropathy [ICD-11: GB55]
Responsed Drug SR8278 Preclinical
 Drug Info 
Responsed Regulator Nuclear receptor subfamily 1 group D member 1 (NR1D1) Driver
 Regulator Info 
Pathway Response Ferroptosis hsa04216
Glutathione metabolism hsa00480
Cell Process Cell ferroptosis
In Vitro Model mRTECs (Mouse renal tubular epithelial cells)
M4100-57 (Mouse renal tubular epithelial cells)
In Vivo Model
Wild-type C57BL/6 mice (eight-week-old, male) were obtained from SPF Biotechnology (Beijing, China). Three sets of animal experiments were performed. In the first set of experiments, male wild-type mice (eight-week-old) were randomly assigned to three groups (n = 6 per group): control group, 2.5 mg/kg AAI group, and 5 mg/kg AAI group. The AAI groups of mice were intraperitoneally injected with AAI (2.5 or 5 mg/kg) once daily for 5 days. The control group of mice were treated with vehicle (corn oil). In the second set of experiments, male Rev-erbfl/fl and Rev-erbkKO mice (eight-week-old) were treated with AAI (5 mg/kg) or vehicle once daily for 5 days by intraperitoneal injection. In the third set of experiments, male wild-type mice (eight-week-old) were randomly divided into the following four groups (n = 6 per group): AAI + SR8278, AAI + DFO, AAI, and vehicle.

    Click to Show/Hide
Response regulation Renal REV-ERB protein was significantly increased in aristolochic acid I-treated mice. Furthermore, knockdown of Rev-erb by siRNA or SR8278 (a REV-ERB antagonist) treatment attenuated ALI-induced ferroptosis in mRTECs. SR8278 treatment enhanced the cell survival and GPX4 expression in ALI-treated mRTECs. Taken together, small molecule antagonism of REV-ERB alleviates aristolochic acid I-induced renal injury probably through inhibiting ferroptosis in mice.
Nuclear factor erythroid 2-related factor 2 (NFE2L2)
 Target Info 
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis-centered Disease Response by This Target [2]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Aristolochic acid nephropathy [ICD-11: GB55]
Responsed Drug Aristololactam Investigative
 Drug Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model HK-2 cells Normal Homo sapiens CVCL_0302
Response regulation Long-term administration of medicine-containing Aristolactam I (ALI) was reported to be related to aristolochic acid nephropathy (AAN), which was attributed to ALI-induced nephrotoxicity. ALI dose-dependently inhibited these protein contents of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and glutathione peroxidase 4 (GPX4), which could be partly rescued by Tin-protoporphyrin IX (SnPP) and mitoTEMPO co-treatment.
References
Ref 1 Involvement of REV-ERB dysregulation and ferroptosis in aristolochic acid I-induced renal injury. Biochem Pharmacol. 2021 Nov;193:114807. doi: 10.1016/j.bcp.2021.114807. Epub 2021 Oct 19.
Ref 2 Mitochondrial Iron Overload-Mediated Inhibition of Nrf2-HO-1/GPX4 Assisted ALI-Induced Nephrotoxicity. Front Pharmacol. 2021 Jan 21;11:624529. doi: 10.3389/fphar.2020.624529. eCollection 2020.