Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Pregnane X receptor activation alleviates renal fibrosis in mice via interacting with p53 and inhibiting the Wnt7a/β-catenin signaling

Acta Pharmacologica Sinica volume 44, pages 2075–2090 (2023)Cite this article

Abstract

Renal fibrosis is a common pathological feature of chronic kidney disease (CKD) with various etiologies, which seriously affects the structure and function of the kidney. Pregnane X receptor (PXR) is a member of the nuclear receptor superfamily and plays a critical role in regulating the genes related to xenobiotic and endobiotic metabolism in mammals. Previous studies show that PXR is expressed in the kidney and has protective effect against acute kidney injury (AKI). In this study, we investigated the role of PXR in CKD. Adenine diet-induced CKD (AD) model was established in wild-type and PXR humanized (hPXR) mice, respectively, which were treated with pregnenolone-16α-carbonitrile (PCN, 50 mg/kg, twice a week for 4 weeks) or rifampicin (RIF, 10 mg·kg−1·d−1, for 4 weeks). We showed that both PCN and RIF, which activated mouse and human PXR, respectively, improved renal function and attenuated renal fibrosis in the two types of AD mice. In addition, PCN treatment also alleviated renal fibrosis in unilateral ureter obstruction (UUO) mice. On the contrary, PXR gene deficiency exacerbated renal dysfunction and fibrosis in both adenine- and UUO-induced CKD mice. We found that PCN treatment suppressed the expression of the profibrotic Wnt7a and β-catenin in AD mice and in cultured mouse renal tubular epithelial cells treated with TGFβ1 in vitro. We demonstrated that PXR was colocalized and interacted with p53 in the nuclei of tubular epithelial cells. Overexpression of p53 increased the expression of Wnt7a, β-catenin and its downstream gene fibronectin. We further revealed that p53 bound to the promoter of Wnt7a gene to increase its transcription and β-catenin activation, leading to increased expression of the downstream profibrotic genes, which was inhibited by PXR. Taken together, PXR activation alleviates renal fibrosis in mice via interacting with p53 and inhibiting the Wnt7a/β-catenin signaling pathway.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: PXR activation by PCN alleviates mouse renal damage induced by adenine.
Fig. 2: PXR activation by PCN attenuates renal fibrosis induced by adenine.
Fig. 3: PXR activation by rifampicin alleviates adenine-induced renal damage in PXR-humanized mice.
Fig. 4: PXR activation by rifampicin alleviates renal fibrosis induced by adenine in PXR-humanized mice.
Fig. 5: PXR gene ablation exacerbates adenine-induced renal damages.
Fig. 6: PXR gene ablation exacerbates adenine-induced renal fibrosis.
Fig. 7: PXR activation inhibits the Wnt7a/β-catenin signaling in the kidneys of adenine-treated mice.
Fig. 8: PXR activation and overexpression inhibit TGFβ1-induced fibrotic gene expression in cultured MTEC.
Fig. 9: PXR activation and overexpression inhibit the Wnt7a/β-catenin signaling in cultured MTEC.
Fig. 10: PXR physically interacts with p53 protein and inhibits p53-induced Wnt7a gene transcription and β-catenin activation.
Fig. 11: Proposed mechanisms by which PXR alleviates kidney fibrosis through interacting with p53.

Similar content being viewed by others

References

  1. Stenvinkel P, Chertow GM, Devarajan P, Levin A, Andreoli SP, Bangalore S, et al. Chronic inflammation in chronic kidney disease progression: role of Nrf2. Kidney Int Rep. 2021;6:1775–87. https://doi.org/10.1016/j.ekir.2021.04.023.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Neovius M, Jacobson SH, Eriksson JK, Elinder CG, Hylander B. Mortality in chronic kidney disease and renal replacement therapy: a population-based cohort study. BMJ Open. 2014;4:e004251. https://doi.org/10.1136/bmjopen-2013-004251.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Jha V, Garcia-Garcia G, Iseki K, Li Z, Naicker S, Plattner B, et al. Chronic kidney disease: global dimension and perspectives. Lancet. 2013;382:260–72. https://doi.org/10.1016/s0140-6736(13)60687-x.

    Article  PubMed  Google Scholar 

  4. Tonelli M, Wiebe N, Culleton B, House A, Rabbat C, Fok M, et al. Chronic kidney disease and mortality risk: a systematic review. J Am Soc Nephrol. 2006;17:2034–47. https://doi.org/10.1681/asn.2005101085.

    Article  PubMed  Google Scholar 

  5. Reidy K, Kang HM, Hostetter T, Susztak K. Molecular mechanisms of diabetic kidney disease. J Clin Invest. 2014;124:2333–40. https://doi.org/10.1172/jci72271.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Miguel V, Tituana J, Herrero JI, Herrero L, Serra D, Cuevas P, et al. Renal tubule Cpt1a overexpression protects from kidney fibrosis by restoring mitochondrial homeostasis. J Clin Invest. 2021;131. https://doi.org/10.1172/jci140695.

  7. Edeling M, Ragi G, Huang S, Pavenstadt H, Susztak K. Developmental signalling pathways in renal fibrosis: the roles of Notch, Wnt and Hedgehog. Nat Rev Nephrol. 2016;12:426–39. https://doi.org/10.1038/nrneph.2016.54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Piersma B, Bank RA, Boersema M. Signaling in fibrosis: TGF-beta, WNT, and YAP/TAZ converge. Front Med. 2015;2:59 https://doi.org/10.3389/fmed.2015.00059.

    Article  Google Scholar 

  9. Urban ML, Manenti L, Vaglio A. Fibrosis–a common pathway to organ injury and failure. N Engl J Med. 2015;373:95–6. https://doi.org/10.1056/NEJMc1504848.

    Article  PubMed  Google Scholar 

  10. Logan CY, Nusse R. The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol. 2004;20:781–810. https://doi.org/10.1146/annurev.cellbio.20.010403.113126.

    Article  CAS  PubMed  Google Scholar 

  11. Zuo Y, Liu Y. New insights into the role and mechanism of Wnt/beta-catenin signalling in kidney fibrosis. Nephrology. 2018;23:38–43. https://doi.org/10.1111/nep.13472.

    Article  CAS  PubMed  Google Scholar 

  12. Feng Y, Ren J, Gui Y, Wei W, Shu B, Lu Q, et al. Wnt/beta-catenin-promoted macrophage alternative activation contributes to kidney fibrosis. J Am Soc Nephrol. 2018;29:182–93. https://doi.org/10.1681/asn.2017040391.

    Article  CAS  PubMed  Google Scholar 

  13. Surendran K, Schiavi S, Hruska KA. Wnt-dependent beta-catenin signaling is activated after unilateral ureteral obstruction, and recombinant secreted frizzled-related protein 4 alters the progression of renal fibrosis. J Am Soc Nephrol. 2005;16:2373–84. https://doi.org/10.1681/asn.2004110949.

    Article  CAS  PubMed  Google Scholar 

  14. Breyer MD, Susztak K. The next generation of therapeutics for chronic kidney disease. Nat Rev Drug Discov. 2016;15:568–88. https://doi.org/10.1038/nrd.2016.67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Dolman ME, Harmsen S, Storm G, Hennink WE, Kok RJ. Drug targeting to the kidney: advances in the active targeting of therapeutics to proximal tubular cells. Adv Drug Deliv Rev. 2010;62:1344–57. https://doi.org/10.1016/j.addr.2010.07.011.

    Article  CAS  PubMed  Google Scholar 

  16. Luan ZL, Zhang C, Ming WH, Huang YZ, Guan YF, Zhang XY. Nuclear receptors in renal health and disease. EBioMedicine. 2022;76:103855. https://doi.org/10.1016/j.ebiom.2022.103855.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Marek CJ, Tucker SJ, Konstantinou DK, Elrick LJ, Haefner D, Sigalas C, et al. Pregnenolone-16alpha-carbonitrile inhibits rodent liver fibrogenesis via PXR (pregnane X receptor)-dependent and PXR-independent mechanisms. Biochem J. 2005;387:601–8. https://doi.org/10.1042/bj20041598.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Wright MC. The impact of pregnane X receptor activation on liver fibrosis. Biochem Soc Trans. 2006;34:1119–23. https://doi.org/10.1042/bst0341119.

    Article  CAS  PubMed  Google Scholar 

  19. Haughton EL, Tucker SJ, Marek CJ, Durward E, Leel V, Bascal Z, et al. Pregnane X receptor activators inhibit human hepatic stellate cell transdifferentiation in vitro. Gastroenterology. 2006;131:194–209. https://doi.org/10.1053/j.gastro.2006.04.012.

    Article  CAS  PubMed  Google Scholar 

  20. Luan Z, Wei Y, Huo X, Sun X, Zhang C, Ming W, et al. Pregnane X receptor (PXR) protects against cisplatin-induced acute kidney injury in mice. Biochim Biophys Acta Mol Basis Dis. 2021;1867:165996. https://doi.org/10.1016/j.bbadis.2020.165996.

    Article  CAS  PubMed  Google Scholar 

  21. Yu X, Xu M, Meng X, Li S, Liu Q, Bai M, et al. Nuclear receptor PXR targets AKR1B7 to protect mitochondrial metabolism and renal function in AKI. Sci Transl Med. 2020;12. https://doi.org/10.1126/scitranslmed.aay7591.

  22. Luan ZL, Ming WH, Sun XW, Zhang C, Zhou Y, Zheng F, et al. A naturally occurring FXR agonist, alisol B 23-acetate, protects against renal ischemia-reperfusion injury. Am J Physiol Ren Physiol. 2021;321:F617–F28. https://doi.org/10.1152/ajprenal.00193.2021.

    Article  CAS  Google Scholar 

  23. Tie L, Xiao H, Wu DL, Yang Y, Wang P. A brief guide to good practices in pharmacological experiments: Western blotting. Acta Pharmacol Sin. 2021;42:1015–7. https://doi.org/10.1038/s41401-020-00539-7.

    Article  CAS  PubMed  Google Scholar 

  24. Schley G, Klanke B, Kalucka J, Schatz V, Daniel C, Mayer M, et al. Mononuclear phagocytes orchestrate prolyl hydroxylase inhibition-mediated renoprotection in chronic tubulointerstitial nephritis. Kidney Int. 2019;96:378–96. https://doi.org/10.1016/j.kint.2019.02.016.

    Article  CAS  PubMed  Google Scholar 

  25. Messeguer X, Escudero R, Farre D, Nunez O, Martinez J, Alba MM. PROMO: detection of known transcription regulatory elements using species-tailored searches. Bioinformatics. 2002;18:333–4. https://doi.org/10.1093/bioinformatics/18.2.333.

    Article  CAS  PubMed  Google Scholar 

  26. Farre D, Roset R, Huerta M, Adsuara JE, Rosello L, Alba MM, et al. Identification of patterns in biological sequences at the ALGGEN server: PROMO and MALGEN. Nucleic Acids Res. 2003;31:3651–3. https://doi.org/10.1093/nar/gkg605.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ali BH, Al-Salam S, Al Za’abi M, Waly MI, Ramkumar A, Beegam S, et al. New model for adenine-induced chronic renal failure in mice, and the effect of gum acacia treatment thereon: comparison with rats. J Pharmacol Toxicol Methods. 2013;68:384–93. https://doi.org/10.1016/j.vascn.2013.05.001.

    Article  CAS  PubMed  Google Scholar 

  28. Zhang Q, Liu L, Lin W, Yin S, Duan A, Liu Z, et al. Rhein reverses Klotho repression via promoter demethylation and protects against kidney and bone injuries in mice with chronic kidney disease. Kidney Int. 2017;91:144–56. https://doi.org/10.1016/j.kint.2016.07.040.

    Article  CAS  PubMed  Google Scholar 

  29. Kliewer SA, Moore JT, Wade L, Staudinger JL, Watson MA, Jones SA, et al. An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway. Cell. 1998;92:73–82. https://doi.org/10.1016/s0092-8674(00)80900-9.

    Article  CAS  PubMed  Google Scholar 

  30. Ma Y, Liu D. Activation of pregnane X receptor by pregnenolone 16 alpha-carbonitrile prevents high-fat diet-induced obesity in AKR/J mice. PLoS One. 2012;7:e38734. https://doi.org/10.1371/journal.pone.0038734.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ali BH, Al Salam S, Al Suleimani Y, Al Za’abi M, Abdelrahman AM, Ashique M, et al. Effects of the SGLT-2 inhibitor canagliflozin on adenine-induced chronic kidney disease in rats. Cell Physiol Biochem. 2019;52:27–39. https://doi.org/10.33594/000000003.

    Article  CAS  PubMed  Google Scholar 

  32. Akchurin OM, Kaskel F. Update on inflammation in chronic kidney disease. Blood Purif. 2015;39:84–92. https://doi.org/10.1159/000368940.

    Article  CAS  PubMed  Google Scholar 

  33. Mihai S, Codrici E, Popescu ID, Enciu AM, Albulescu L, Necula LG, et al. Inflammation-related mechanisms in chronic kidney disease prediction, progression, and outcome. J Immunol Res. 2018;2018:2180373. https://doi.org/10.1155/2018/2180373.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Martinez-Klimova E, Aparicio-Trejo OE, Tapia E, Pedraza-Chaverri J. Unilateral ureteral obstruction as a model to investigate fibrosis-attenuating treatments. Biomolecules. 2019;9. https://doi.org/10.3390/biom9040141.

  35. Hassani-Nezhad-Gashti F, Rysa J, Kummu O, Napankangas J, Buler M, Karpale M, et al. Activation of nuclear receptor PXR impairs glucose tolerance and dysregulates GLUT2 expression and subcellular localization in liver. Biochem Pharmacol. 2018;148:253–64. https://doi.org/10.1016/j.bcp.2018.01.001.

    Article  CAS  PubMed  Google Scholar 

  36. Kliewer SA. Nuclear receptor PXR: discovery of a pharmaceutical anti-target. J Clin Invest. 2015;125:1388–9. https://doi.org/10.1172/jci81244.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Miao J, Liu J, Niu J, Zhang Y, Shen W, Luo C, et al. Wnt/beta-catenin/RAS signaling mediates age-related renal fibrosis and is associated with mitochondrial dysfunction. Aging Cell. 2019;18:e13004. https://doi.org/10.1111/acel.13004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Luo C, Zhou S, Zhou Z, Liu Y, Yang L, Liu J, et al. Wnt9a promotes renal fibrosis by accelerating cellular senescence in tubular epithelial cells. J Am Soc Nephrol. 2018;29:1238–56. https://doi.org/10.1681/asn.2017050574.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Chen X, Tan H, Xu J, Tian Y, Yuan Q, Zuo Y, et al. Klotho-derived peptide 6 ameliorates diabetic kidney disease by targeting Wnt/beta-catenin signaling. Kidney Int. 2022;102:506–20. https://doi.org/10.1016/j.kint.2022.04.028.

    Article  CAS  PubMed  Google Scholar 

  40. Higgins SP, Tang Y, Higgins CE, Mian B, Zhang W, Czekay RP, et al. TGF-beta1/p53 signaling in renal fibrogenesis. Cell Signal. 2018;43:1–10. https://doi.org/10.1016/j.cellsig.2017.11.005.

    Article  CAS  PubMed  Google Scholar 

  41. Lee KH, Li M, Michalowski AM, Zhang X, Liao H, Chen L, et al. A genomewide study identifies the Wnt signaling pathway as a major target of p53 in murine embryonic stem cells. Proc Natl Acad Sci USA. 2010;107:69–74. https://doi.org/10.1073/pnas.0909734107.

    Article  PubMed  Google Scholar 

  42. Wang Q, Zou Y, Nowotschin S, Kim SY, Li QV, Soh CL, et al. The p53 family coordinates Wnt and nodal inputs in mesendodermal differentiation of embryonic stem cells. Cell Stem Cell. 2017;20:70–86. https://doi.org/10.1016/j.stem.2016.10.002.

    Article  CAS  PubMed  Google Scholar 

  43. Yan L, Chen Z, Wu L, Su Y, Wang X, Tang N. Inhibitory effect of PXR on ammonia-induced hepatocyte autophagy via P53. Toxicol Lett. 2018;295:153–61. https://doi.org/10.1016/j.toxlet.2018.06.1066.

    Article  CAS  PubMed  Google Scholar 

  44. Liu Y. Cellular and molecular mechanisms of renal fibrosis. Nat Rev Nephrol. 2011;7:684–96. https://doi.org/10.1038/nrneph.2011.149.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Watanabe A, Marumo T, Kawarazaki W, Nishimoto M, Ayuzawa N, Ueda K, et al. Aberrant DNA methylation of pregnane X receptor underlies metabolic gene alterations in the diabetic kidney. Am J Physiol Ren Physiol. 2018;314:F551–F60. https://doi.org/10.1152/ajprenal.00390.2017.

    Article  CAS  Google Scholar 

  46. Congiu M, Mashford ML, Slavin JL, Desmond PV. Coordinate regulation of metabolic enzymes and transporters by nuclear transcription factors in human liver disease. J Gastroenterol Hepatol. 2009;24:1038–44. https://doi.org/10.1111/j.1440-1746.2009.05800.x.

    Article  CAS  PubMed  Google Scholar 

  47. Hanada K, Nakai K, Tanaka H, Suzuki F, Kumada H, Ohno Y, et al. Effect of nuclear receptor downregulation on hepatic expression of cytochrome P450 and transporters in chronic hepatitis C in association with fibrosis development. Drug Metab Pharmacokinet. 2012;27:301–6. https://doi.org/10.2133/dmpk.dmpk-11-rg-077.

    Article  CAS  PubMed  Google Scholar 

  48. Wallace K, Cowie DE, Konstantinou DK, Hill SJ, Tjelle TE, Axon A, et al. The PXR is a drug target for chronic inflammatory liver disease. J Steroid Biochem Mol Biol. 2010;120:137–48. https://doi.org/10.1016/j.jsbmb.2010.04.012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. He W, Dai C, Li Y, Zeng G, Monga SP, Liu Y. Wnt/beta-catenin signaling promotes renal interstitial fibrosis. J Am Soc Nephrol. 2009;20:765–76. https://doi.org/10.1681/asn.2008060566.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Zhou L, Li Y, Zhou D, Tan RJ, Liu Y. Loss of Klotho contributes to kidney injury by derepression of Wnt/beta-catenin signaling. J Am Soc Nephrol. 2013;24:771–85. https://doi.org/10.1681/asn.2012080865.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Xiao L, Zhou D, Tan RJ, Fu H, Zhou L, Hou FF, et al. Sustained activation of Wnt/beta-catenin signaling drives AKI to CKD progression. J Am Soc Nephrol. 2016;27:1727–40. https://doi.org/10.1681/asn.2015040449.

    Article  CAS  PubMed  Google Scholar 

  52. Rooney B, O’Donovan H, Gaffney A, Browne M, Faherty N, Curran SP, et al. CTGF/CCN2 activates canonical Wnt signalling in mesangial cells through LRP6: implications for the pathogenesis of diabetic nephropathy. FEBS Lett. 2011;585:531–8. https://doi.org/10.1016/j.febslet.2011.01.004.

    Article  CAS  PubMed  Google Scholar 

  53. Ren S, Johnson BG, Kida Y, Ip C, Davidson KC, Lin SL, et al. LRP-6 is a coreceptor for multiple fibrogenic signaling pathways in pericytes and myofibroblasts that are inhibited by DKK-1. Proc Natl Acad Sci USA. 2013;110:1440–5. https://doi.org/10.1073/pnas.1211179110.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Overstreet JM, Gifford CC, Tang J, Higgins PJ, Samarakoon R. Emerging role of tumor suppressor p53 in acute and chronic kidney diseases. Cell Mol Life Sci. 2022;79:474. https://doi.org/10.1007/s00018-022-04505-w.

    Article  CAS  PubMed  Google Scholar 

  55. Ma Z, Li L, Livingston MJ, Zhang D, Mi Q, Zhang M, et al. p53/microRNA-214/ULK1 axis impairs renal tubular autophagy in diabetic kidney disease. J Clin Invest. 2020;130:5011–26. https://doi.org/10.1172/jci135536.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Patel S, Tang J, Overstreet JM, Anorga S, Lian F, Arnouk A, et al. Rac-GTPase promotes fibrotic TGF-beta1 signaling and chronic kidney disease via EGFR, p53, and Hippo/YAP/TAZ pathways. FASEB J. 2019;33:9797–810. https://doi.org/10.1096/fj.201802489RR.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Li C, Xie N, Li Y, Liu C, Hou FF, Wang J. N-acetylcysteine ameliorates cisplatin-induced renal senescence and renal interstitial fibrosis through sirtuin1 activation and p53 deacetylation. Free Radic Biol Med. 2019;130:512–27. https://doi.org/10.1016/j.freeradbiomed.2018.11.006.

    Article  CAS  PubMed  Google Scholar 

  58. Ying Y, Kim J, Westphal SN, Long KE, Padanilam BJ. Targeted deletion of p53 in the proximal tubule prevents ischemic renal injury. J Am Soc Nephrol. 2014;25:2707–16. https://doi.org/10.1681/asn.2013121270.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Overstreet JM, Samarakoon R, Meldrum KK, Higgins PJ. Redox control of p53 in the transcriptional regulation of TGF-beta1 target genes through SMAD cooperativity. Cell Signal. 2014;26:1427–36. https://doi.org/10.1016/j.cellsig.2014.02.017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Xiao Q, Werner J, Venkatachalam N, Boonekamp KE, Ebert MP, Zhan T. Cross-talk between p53 and Wnt signaling in cancer. Biomolecules. 2022;12. https://doi.org/10.3390/biom12030453.

  61. Han D, Xu Y, Peng WP, Feng F, Wang Z, Gu C, et al. Citrus alkaline extracts inhibit senescence of A549 cells to alleviate pulmonary fibrosis via the beta-catenin/P53 pathway. Med Sci Monit. 2021;27:e928547. https://doi.org/10.12659/msm.928547.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Gu Z, Tan W, Feng G, Meng Y, Shen B, Liu H, et al. Wnt/beta-catenin signaling mediates the senescence of bone marrow-mesenchymal stem cells from systemic lupus erythematosus patients through the p53/p21 pathway. Mol Cell Biochem. 2014;387:27–37. https://doi.org/10.1007/s11010-013-1866-5.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Prof. Nan-hong Tang for providing pcDNA3.0-p53 expression vector. This work was supported by the National Key R&D Program of China (2020YFC2005000 to XYZ and YFG); the National Natural Science Foundation of China (82270703 to XYZ, 81970606 to XYZ, and 81970595 to YFG); and the East China Normal University Medicine and Health Joint Fund (2022JKXYD03001 to XYZ).

Author information

Authors and Affiliations

  1. Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, 116044, China

    Wen-hua Ming, Zhi-lin Luan, Cong Zhang, Yi-hang Zhao, Ying-zhi Huang, Rong-fang Qiao, Hu Xu & You-fei Guan

  2. Health Science Center, East China Normal University, Shanghai, 200241, China

    Wen-hua Ming, Hang-chi Liu, Xiao-wan Sun & Xiao-yan Zhang

  3. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China

    Zhi-lin Luan, Hu Xu & You-fei Guan

  4. Dalian Key Laboratory for Nuclear Receptors in Major Metabolic Diseases, Dalian, 116044, China

    Zhi-lin Luan, Hu Xu & You-fei Guan

  5. Department of nephrology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226006, China

    Yao Yao & Shu-yuan Hu

  6. Division of Nephrology, Wuhu Hospital, East China Normal University, Wuhu, 241100, China

    Chun-xiu Du & Xiao-yan Zhang

Authors
  1. Wen-hua Ming
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhi-lin Luan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yao Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hang-chi Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shu-yuan Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Chun-xiu Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Cong Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yi-hang Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ying-zhi Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Xiao-wan Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Rong-fang Qiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Hu Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. You-fei Guan
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Xiao-yan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

WHM, YFG and XYZ conceived the experiments. WHM, YY, HCL, SYH, CZ, YHZ, YZH, XWS and RFQ performed the experiments and acquired the data. ZLL, HX and CXD analyzed the data. WHM drafted the original manuscript. YFG and XYZ contributed to the conception of the study and revised the manuscript. All authors approved the final manuscript and agreed to be accountable for all aspects of the work.

Corresponding authors

Correspondence to You-fei Guan or Xiao-yan Zhang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval

The use of animals and the study protocols were reviewed and approved by the Animal Care and Use Review Committee of Dalian Medical University (AEE22128).

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ming, Wh., Luan, Zl., Yao, Y. et al. Pregnane X receptor activation alleviates renal fibrosis in mice via interacting with p53 and inhibiting the Wnt7a/β-catenin signaling. Acta Pharmacol Sin 44, 2075–2090 (2023). https://doi.org/10.1038/s41401-023-01113-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41401-023-01113-7

Keywords

This article is cited by

Search

Advanced search

Quick links