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Role of CREB1 dysregulation in calcium oxalate monohydrate crystals-induced tubular epithelial cell injury

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Abstract

Background

Calcium oxalate monohydrate (COM) is a major component of kidney stones and can induce the injury of renal tubular epithelial cells (RTECs).

Objectives

This study aimed to investigate the role of cAMP response element-binding protein 1 (CREB1) in COM-induced RTEC injury.

Results

CREB1 and phosphorylated CREB1 (p-CREB1) were upregulated in COM-induced RTECs. CREB1 upregulation attenuated COM-induced oxidative stress, inflammatory responses, and cell injury. CREB1 bound to the MLKL promoter and transcriptionally repressed MLKL expression. MLKL upregulation reversed the inhibitory role of CREB1 overexpression in RTEC injury.

Conclusions

CREB1 repressed MLKL expression to attenuate COM-induced RTEC injury, suggesting that CREB1 may be a therapeutic target for kidney stone disease.

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Data availability

Data will be made available on request.

References

  • Alexander RT, Fuster DG, Dimke H (2022) Mechanisms underlying calcium nephrolithiasis. Annu Rev Physiol 84:559–583

    Article  CAS  PubMed  Google Scholar 

  • Arany I, Megyesi JK, Reusch JE, Safirstein RL (2005) CREB mediates ERK-induced survival of mouse renal tubular cells after oxidant stress. Kidney Int 68:1573–1582

    Article  PubMed  Google Scholar 

  • Barnett M, Hall S, Dixit M, Arany I (2016) Simvastatin attenuates oleic acid-induced oxidative stress through CREB-dependent induction of heme oxygenase-1 in renal proximal tubule cells. Pediatr Res 79:243–250

    Article  CAS  PubMed  Google Scholar 

  • Castro-Mondragon JA et al (2022) JASPAR 2022: the 9th release of the open-access database of transcription factor binding profiles. Nucleic Acids Res 50:D165–D173

    Article  CAS  PubMed  Google Scholar 

  • Chen Y, Yang Y, Liu Z, He L (2022) Adiponectin promotes repair of renal tubular epithelial cells by regulating mitochondrial biogenesis and function. Metabolism 128:154959

    Article  CAS  PubMed  Google Scholar 

  • Chia YL et al (2014) Inhibition of human cytomegalovirus replication by overexpression of CREB1. Antiviral Res 102:11–22

    Article  CAS  PubMed  Google Scholar 

  • Dubreuil JD et al (1990) Purification, characterization, and localization of a protein antigen shared by thermophilic campylobacters. J Clin Microbiol 28:1321–1328

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goldspink PH, Russell B (1994) The cAMP response element binding protein is expressed and phosphorylated in cardiac myocytes. Circ Res 74:1042–1049

    Article  CAS  PubMed  Google Scholar 

  • Jiang L et al (2019) hsa-miR-500a-3P alleviates kidney injury by targeting MLKL-mediated necroptosis in renal epithelial cells. FASEB J 33:3523–3535

    Article  CAS  PubMed  Google Scholar 

  • Jiang A, Song A, Zhang C (2022) Modes of podocyte death in diabetic kidney disease: an update. J Nephrol 35:1571–1584

    Article  CAS  PubMed  Google Scholar 

  • Khan SR (2004) Role of renal epithelial cells in the initiation of calcium oxalate stones. Nephron Exp Nephrol 98:e55-60

    Article  CAS  PubMed  Google Scholar 

  • Lee B, Shim I, Lee H, Hahm DH (2018) Melatonin ameliorates cognitive memory by regulation of cAMP-response element-binding protein expression and the anti-inflammatory response in a rat model of post-traumatic stress disorder. BMC Neurosci 19:38

    Article  PubMed  PubMed Central  Google Scholar 

  • Leopold Wager CM et al (2023) Activation of transcription factor CREB in human macrophages by Mycobacterium tuberculosis promotes bacterial survival, reduces NF-kB nuclear transit and limits phagolysosome fusion by reduced necroptotic signaling. PLoS Pathog 19:e1011297

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lim J et al (2020) Glutathione dynamics determine the therapeutic efficacy of mesenchymal stem cells for graft-versus-host disease via CREB1-NRF2 pathway. Sci Adv 6:eaba1334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu Y et al (2019) MicroRNA expression profile by next-generation sequencing in a novel rat model of contrast-induced acute kidney injury. Ann Transl Med 7:178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(−delta delta C(T)) method. Methods 25:402–408

    Article  CAS  PubMed  Google Scholar 

  • Lu Z et al (2021) Necroptosis signaling promotes inflammation, airway remodeling, and emphysema in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 204:667–681

    Article  CAS  PubMed  Google Scholar 

  • Macias-Silva M et al (1996) MADR2 is a substrate of the TGFbeta receptor and its phosphorylation is required for nuclear accumulation and signaling. Cell 87:1215–1224

    Article  CAS  PubMed  Google Scholar 

  • Martens S, Bridelance J, Roelandt R, Vandenabeele P, Takahashi N (2021) MLKL in cancer: more than a necroptosis regulator. Cell Death Differ 28:1757–1772

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ming S et al (2022) Oxalate-induced apoptosis through ERS-ROS-NF-kappaB signalling pathway in renal tubular epithelial cell. Mol Med 28:88

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mulay SR, Anders HJ (2017) Crystal nephropathies: mechanisms of crystal-induced kidney injury. Nat Rev Nephrol 13:226–240

    Article  CAS  PubMed  Google Scholar 

  • Mulay SR et al (2016) Cytotoxicity of crystals involves RIPK3-MLKL-mediated necroptosis. Nat Commun 7:10274

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Murphy JM (2020) The killer pseudokinase mixed lineage kinase domain-like protein (MLKL). Cold Spring Harb Perspect Biol 12:a036376

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shan Q et al (2016) Epigenetic modification of miR-10a regulates renal damage by targeting CREB1 in type 2 diabetes mellitus. Toxicol Appl Pharmacol 306:134–143

    Article  CAS  PubMed  Google Scholar 

  • Sharma VK, Singh TG (2020) CREB: a multifaceted target for Alzheimer’s disease. Curr Alzheimer Res 17:1280–1293

    Article  CAS  PubMed  Google Scholar 

  • Sirotkin AV et al (2018) cAMP response element-binding protein 1 controls porcine ovarian cell proliferation, apoptosis, and FSH and insulin-like growth factor 1 response. Reprod Fertil Dev 30:1145–1153

    Article  CAS  PubMed  Google Scholar 

  • Son J, Lee JH, Kim HN, Ha H, Lee ZH (2010) cAMP-response-element-binding protein positively regulates breast cancer metastasis and subsequent bone destruction. Biochem Biophys Res Commun 398:309–314

    Article  CAS  PubMed  Google Scholar 

  • Srivastava A et al (2022) RIPK3-MLKL signaling activates mitochondrial CaMKII and drives intrarenal extracellular matrix production during CKD. Matrix Biol 112:72–89

    Article  CAS  PubMed  Google Scholar 

  • Stamatelou K, Goldfarb DS (2023) Epidemiology of kidney stones. Healthcare (Basel) 11:424

    Article  PubMed  Google Scholar 

  • Tonnus W et al (2022) Rubicon-deficiency sensitizes mice to mixed lineage kinase domain-like (MLKL)-mediated kidney ischemia-reperfusion injury. Cell Death Dis 13:236

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tsujihata M (2008) Mechanism of calcium oxalate renal stone formation and renal tubular cell injury. Int J Urol 15:115–120

    Article  CAS  PubMed  Google Scholar 

  • Wang D et al (2020) FOXO1 inhibition prevents renal ischemia-reperfusion injury via cAMP-response element binding protein/PPAR-gamma coactivator-1alpha-mediated mitochondrial biogenesis. Br J Pharmacol 177:432–448

    Article  CAS  PubMed  Google Scholar 

  • Wang Z, Zhang Y, Zhang J, Deng Q, Liang H (2021) Recent advances on the mechanisms of kidney stone formation (Review). Int J Mol Med 48:149

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wei J et al (2021) Upregulation of RIP3 promotes necroptosis via a ROS-dependent NF-kappaB pathway to induce chronic inflammation in HK-2 cells. Mol Med Rep 24:783

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wen AY, Sakamoto KM, Miller LS (2010) The role of the transcription factor CREB in immune function. J Immunol 185:6413–6419

    Article  CAS  PubMed  Google Scholar 

  • Wu X et al (2019) NDP-MSH binding melanocortin-1 receptor ameliorates neuroinflammation and BBB disruption through CREB/Nr4a1/NF-kappaB pathway after intracerebral hemorrhage in mice. J Neuroinflammation 16:192

    Article  PubMed  PubMed Central  Google Scholar 

  • Wu X et al (2020) MLKL-dependent signaling regulates autophagic flux in a murine model of non-alcohol-associated fatty liver and steatohepatitis. J Hepatol 73:616–627

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu Y et al (2021) The activation of ROS/NF-kappaB/MMP-9 pathway promotes calcium-induced kidney crystal deposition. Oxid Med Cell Longev 2021:8836355

    Article  PubMed  PubMed Central  Google Scholar 

  • Xie Z, Chen J, Chen Z (2022) MicroRNA-204 attenuates oxidative stress damage of renal tubular epithelial cells in calcium oxalate kidney-stone formation via MUC4-mediated ERK signaling pathway. Urolithiasis 50:1–10

    Article  PubMed  Google Scholar 

  • Xu Y, Han J (2016) The necrosome in acute kidney injury. Semin Nephrol 36:199–207

    Article  CAS  PubMed  Google Scholar 

  • Yang Y, Wang L, Zhang H, Luo L (2022) Mixed lineage kinase domain-like pseudokinase-mediated necroptosis aggravates periodontitis progression. J Mol Med (Berl) 100:77–86

    Article  CAS  PubMed  Google Scholar 

  • Yu L, Gan X, Bai Y, An R (2021) CREB1 protects against the renal injury in a rat model of kidney stone disease and calcium oxalate monohydrate crystals-induced injury in NRK-52E cells. Toxicol Appl Pharmacol 413:115394

    Article  CAS  PubMed  Google Scholar 

  • Zhao X et al (2020) CREB1-induced miR-1204 promoted malignant phenotype of glioblastoma through targeting NR3C2. Cancer Cell Int 20:111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou Y et al (2021) Metformin regulates inflammation and fibrosis in diabetic kidney disease through TNC/TLR4/NF-kappaB/miR-155-5p inflammatory loop. World J Diabetes 12:19–46

    Article  PubMed  PubMed Central  Google Scholar 

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Author notes

  1. Anqing Yang and Jianian Zhang share the first authorship.

Authors and Affiliations

  1. Department of Urology, RuiJin Hospital Lu Wan Branch, Shanghai Jiaotong University School of Medicine, No. 149, South Chongqing Road, Shanghai, 200020, China

    Anqing Yang, Tao Huang, Zhongwei Yu, Chenhui Zhao, Yongzhi Xu & Binbin Ma

  2. Department of Clinical Laboratory Medicine, Shanghai Tenth People’s Hospital of Tongji University, Shanghai, 200072, China

    Jianian Zhang

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  1. Anqing Yang
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Contributions

AY, JZ and ZY conceived the study; AY, JZ and CZ designed the experiments; AY and JZ performed experiments, YX and BM analyzed the data; TH prepared figures; AY wrote the manuscript. All authors contributed to drafting or revising the article, have agreed on the journal to which the article will be submitted, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.

Corresponding author

Correspondence to Binbin Ma.

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Conflict of interest

Anqing Yang declare no conflicts of interest. Jianian Zhang declare no conflicts of interest. Tao Huang declare no conflicts of interest. Zhongwei Yu declare no conflicts of interest. Chenhui Zhao declare no conflicts of interest. Yongzhi Xu declare no conflicts of interest. Binbin Ma declare no conflicts of interest.

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Yang, A., Zhang, J., Huang, T. et al. Role of CREB1 dysregulation in calcium oxalate monohydrate crystals-induced tubular epithelial cell injury. Mol. Cell. Toxicol. (2023). https://doi.org/10.1007/s13273-023-00404-8

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