Urinary Metabolomics and Biomarkers of Aristolochic Acid Nephrotoxicity by UPLC-QTOF/HDMS

Feng

Free Radical Biology and Medicine

et al. 2019

Self Cite

Renal ischemia-reperfusion injury (IRI) is a complex syndrome, which causes chronic kidney disease (CKD) after recovery from IRI-mediated acute kidney injury (AKI). There is no single therapy that could effectively prevent the renal injury after ischemia. In this study, the effects of melatonin or poricoic acid A (PAA) and their combination were investigated in protecting against AKI-to-CKD transition in rats and hypoxia/reoxygenation (H/R)induced injury in cultured renal NRK-52E cells. Melatonin and PAA significantly reduced the magnitude of rise in serum creatinine and urea levels in IRI rats at days 3 and 14. Our results further showed that treatment with melatonin and PAA ameliorated renal fibrosis and podocyte injury by attenuating oxidative stress and inflammation via regulation of nuclear factor-kappa B (NF-κB) and nuclear factor-erythroid-2-related factor 2 (Nrf2) pathways in IRI rats. Melatonin and PAA protected against AKI-to-CKD transition by regulating growth arrest-specific 6 (Gas6)/AxleNFeκB/Nrf2 signaling cascade. Melatonin and PAA initiallyupregulated Gas6/Axl signaling to reduce oxidative stress and inflammation in AKI and subsequently downregulated Gas6/Axl signaling to attenuate renal fibrosis and progression to CKD. Melatonin and PAA inhibited expression of extracellular matrix proteins. Poricoic acid A enhances melatonin-mediated inhibition of AKI-to-CKD transition by the regulating Gas6/AxleNFeκB/Nrf2 signaling cascade. Notably, our study first identified Axl as a promising therapeutic target for prevention of AKI-to-CKD transition.

Section: Discussionmentioning

confidence: 99%

Poricoic acid A enhances melatonin inhibition of AKI-to-CKD transition by regulating Gas6/Axl NF κB/Nrf2 axis

Feng

Free Radical Biology and Medicine

et al. 2019

Self Cite

“…As a holistic approach reflecting comprehensive changes of endogenous metabolites in bio-fluids and tissues, metabolomics has been widely applied to the study of the pathogenesis of nephrotoxicity or kidney diseases and discover new biomarkers as well as effect of drug intervention and therapeutic mechanism 1–4 . Metabolomic method was widely used to explore the nephrotoxicity induced by chemical drugs 5, 6 and natural products 7–10 . Traditional Chinese medicines (TCMs) have been used for the treatment of different kidney diseases for thousands of years.…”

Section: Introductionmentioning

confidence: 99%

Urinary metabolomics reveals the therapeutic effect of HuangQi Injections in cisplatin-induced nephrotoxic rats

Song

Wang

et al. 2017

Sci Rep

The side effects of cisplatin (CDDP), notably nephrotoxicity, greatly limited its use in clinical chemotherapy. HuangQi Injections (HI), a commonly used preparation of the well-known Chinese herbal medicine Astragali radix, appeared to be promising treatment for nephrotoxicity without compromising the anti-tumor activity of CDDP. In this study, the urinary metabolomics approach using liquid chromatography time of flight mass spectrometry (LC-TOF/MS) was developed to assess the toxicity-attenuation effects and corresponding mechanisms of HI on CDDP-exposed rats. As a result, successive administration of HI significantly recovered the decline of body weight and downregulated the abnormal increase of serum creatinine and urea. HI partly restored the CDDP-induced alteration of metabolic profiling back into normal condition. Totally 43 toxicity-attenuation potential biomarkers were screened and tentatively identified, which were involved in important metabolic pathways such as amino acid metabolism, TCA cycle, fatty acid metabolism, vitamin B6 metabolism and purine metabolism. The results clearly revealed that HI could alleviate CDDP-induced nephrotoxicity and improve the disturbed metabolic balance induced by repeated CDDP exposure. The present study provided reliable evidence for the protective effect of HI on CDDP-induced toxicity with the multi-target pharmacological characteristics.

“…PAG is a metabolite influenced by gut flora. Prior studies using models of adenine and aristolochic acid renal damage, have reported an increased excretion of PAG in urine (Zhang et al 2015;Zhao et al 2015). In this study, the signal of PAG was one of the variables contributing to the separation of the FAIG-Mo group, but its intensity in urine decreased in comparison to the control group.…”

Section: Discussionmentioning

confidence: 49%

Peer Review #2 of "Metabolomic and biochemical characterization of a new model of the transition of acute kidney injury to chronic kidney disease induced by folic acid (v0.2)"

Zhao¹

2019