PMID- 36081929 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20220912 IS - 1663-9812 (Print) IS - 1663-9812 (Electronic) IS - 1663-9812 (Linking) VI - 13 DP - 2022 TI - Oroxylin A ameliorates AKI-to-CKD transition through maintaining PPARalpha-BNIP3 signaling-mediated mitochondrial homeostasis. PG - 935937 LID - 10.3389/fphar.2022.935937 [doi] LID - 935937 AB - Background: Acute kidney injury (AKI) occurs in approximately 7-18% of all hospitalizations, but there are currently no effective drug therapy for preventing AKI or delaying its progression to chronic kidney disease (CKD). Recent studies have shown that Scutellaria baicalensis, a traditional Chinese herb, could attenuate cisplatin-induced AKI, although the mechanism remains elusive. Further, it is unknown whether its major active component, Oroxylin A (OA), can alleviate kidney injury. Methods: The therapeutic effect of OA was evaluated by using ischemia-reperfusion (IR) and cisplatin mediated-AKI mice and HK-2 cells under hypoxia-reoxygenation (HR) conditions. HE staining, transmission electron microscopy, flow cytometry, immunofluorescence, qPCR, Western blot, PPARalpha inhibitor, BNIP3 siRNA and ChIP assay were used to explore the role and mechanism of OA in AKI. Results: OA ameliorated tubular damage and dramatically decreased serum creatinine (Scr) and urea nitrogen (BUN), and the expressions of renal injury markers (Kim-1, Ngal) in AKI mice induced by both IR injury and cisplatin, as well as attenuating AKI-to-CKD transition. In vitro experiments showed that OA alleviated HR-induced mitochondrial homeostasis imbalance in renal tubular epithelial cells. Mechanistically, OA dose-dependently induced the expression of Bcl-2/adenovirus E1B 19-kDa interacting protein (BNIP3), while knockdown of BNIP3 expression reversed the protection of OA against HR-mediated mitochondrial injury. Network pharmacological analysis and experimental validation suggested that OA enhanced BNIP3 expression via upregulating the expression of peroxisome proliferator activated receptor alpha (PPARalpha), which induced the transcription of BNIP3 via directly binding to its promoter region. Both in vitro and in vivo experiments confirmed that the renoprotective effect of OA was dramatically reduced by GW6471, a PPARalpha antagonist. Conclusion: Our findings revealed that OA ameliorates AKI-to-CKD transition by maintaining mitochondrial homeostasis through inducing PPARalpha-BNIP3 signaling pathway, indicating that OA may serve as a candidate therapeutic strategy for alleviating AKI and CKD. CI - Copyright (c) 2022 Yao, Qin, Xiong, Xin, Guan, Gong, Chen, Liu, Zhang, Zhao and Huang. FAU - Yao, Mengying AU - Yao M AD - School of Medicine, Chongqing University, Chongqing, China. AD - Department of Nephrology, The Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China. FAU - Qin, Shaozong AU - Qin S AD - Department of Nephrology, The Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China. FAU - Xiong, Jiachuan AU - Xiong J AD - Department of Nephrology, The Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China. FAU - Xin, Wang AU - Xin W AD - Department of Nephrology, The Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China. FAU - Guan, Xu AU - Guan X AD - Department of Nephrology, The Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China. FAU - Gong, Shuiqin AU - Gong S AD - Department of Nephrology, The Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China. FAU - Chen, Jing AU - Chen J AD - Department of Nephrology, The Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China. FAU - Liu, Yong AU - Liu Y AD - Department of Nephrology, The Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China. FAU - Zhang, Bo AU - Zhang B AD - Department of Nephrology, The Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China. FAU - Zhao, Jinghong AU - Zhao J AD - Department of Nephrology, The Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China. FAU - Huang, Yinghui AU - Huang Y AD - Department of Nephrology, The Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China. AD - School of Medicine, Chongqing University, Chongqing, China. LA - eng PT - Journal Article DEP - 20220823 PL - Switzerland TA - Front Pharmacol JT - Frontiers in pharmacology JID - 101548923 PMC - PMC9445212 OTO - NOTNLM OT - BNIP3 OT - PPARalpha OT - acute kidney injury OT - mitochondrial energy metabolism OT - oroxylin A COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2022/09/10 06:00 MHDA- 2022/09/10 06:01 PMCR- 2022/08/23 CRDT- 2022/09/09 02:16 PHST- 2022/05/04 00:00 [received] PHST- 2022/07/12 00:00 [accepted] PHST- 2022/09/09 02:16 [entrez] PHST- 2022/09/10 06:00 [pubmed] PHST- 2022/09/10 06:01 [medline] PHST- 2022/08/23 00:00 [pmc-release] AID - 935937 [pii] AID - 10.3389/fphar.2022.935937 [doi] PST - epublish SO - Front Pharmacol. 2022 Aug 23;13:935937. doi: 10.3389/fphar.2022.935937. eCollection 2022.