Skip to main content
SpringerLink
Log in

The Footprints of Mitochondrial Fission and Apoptosis in Fluoride-Induced Renal Dysfunction

  • Research
  • Published:
Biological Trace Element Research Aims and scope Submit manuscript

Abstract

Fluoride (F) is widely distributed in the environment and poses serious health risks to humans and animals. Although a good body of literature demonstrates a close relationship between F content and renal system performance, there is no satisfactory information on the involved intracellular routes. Hence, this study used histopathology and mitochondrial fission to explore fluorine-induced nephrotoxicity further. For this purpose, mice were exposed to the F ion (0, 25, 50, 100 mg/L) for 90 days. The effects of different F levels on renal pathomorphology and ion metabolism were assessed using hematoxylin and eosin (H&E), periodic acid-Schiff stain (PAS), periodic acid-silver methenamine (PASM), Prussian blue (PB), and alkaline phosphatase (ALP) staining. The results showed that F could lead to glomerular atrophy, tubular degeneration, and vacuolization. Meanwhile, F also could increase glomerular and tubular glycoproteins; made thickening of the renal capsule membrane and thickening of the tubular basement membrane; led to the accumulation of iron ions in the tubules; and increased in glomerular alp and decreased tubular alp. Concomitantly, IHC results showed that F significantly upregulated the expression levels of mitochondrial fission-related proteins, including mitochondrial fission factor (Mff), fission 1 (Fis1), and mitochondrial dynamics proteins of 49 kDa (MiD49) and 51 kDa (MiD51), ultimately caused apoptosis. To sum up, excessive fluorine has a strong nephrotoxicity effect, disrupting the balance of mitochondrial fission and fusion, interfering with the process of mitochondrial fission, and then causing damage to renal tissue structure and apoptosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Data Availability

All data generated or analyzed during this study are included in this published article.

Code Availability

Not applicable.

References

  1. Guo Z, Wang M, Dai H, Pan S (2023) Contamination status and ecological security thresholds of fluoride in farmland around a phosphorus chemical plant in a karst area of southwestern China. Toxics 11:587. https://doi.org/10.3390/toxics11070587

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Tecklenborg J, Clayton D, Siebert S, Coley SM (2018) The role of the immune system in kidney disease. Clin Exp Immunol 192:142–150. https://doi.org/10.1111/cei.13119

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Siamopoulos KC, Kalaitzidis RG (2008) Inhibition of the renin–angiotensin system and chronic kidney disease. Int Urol Nephrol 40:1015–1025. https://doi.org/10.1007/s11255-008-9424-x

    Article  CAS  PubMed  Google Scholar 

  4. Taylor JM, Gardner DE, Scott JK, Maynard EA, Downs WL, Smith FA, Hodge HC (1961) Toxic effects of fluoride on the rat kidney. II. Chronic effects. Toxicol Appl Pharmacol 3:290–314. https://doi.org/10.1016/0041-008x(61)90068-0

    Article  CAS  PubMed  Google Scholar 

  5. Perera T, Ranasinghe S, Alles N, Waduge R (2018) Effect of fluoride on major organs with the different time of exposure in rats. Environ Health Prev Med 23:17. https://doi.org/10.1186/s12199-018-0707-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Wimalawansa SJ (2014) Escalating chronic kidney diseases of multi-factorial origin in Sri Lanka: causes, solutions, and recommendations. Environ Health Prev Med 19:375–394. https://doi.org/10.1007/s12199-014-0395-5

    Article  PubMed  PubMed Central  Google Scholar 

  7. Dharmaratne RW (2015) Fluoride in drinking water and diet: the causative factor of chronic kidney diseases in the North Central Province of Sri Lanka. Environ Health Prev Med 20:237–242. https://doi.org/10.1007/s12199-015-0464-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Caglayan C, Kandemir FM, Darendelioğlu E, Küçükler S, Ayna A (2021) Hesperidin protects liver and kidney against sodium fluoride-induced toxicity through anti-apoptotic and anti-autophagic mechanisms. Life Sci 281:119730. https://doi.org/10.1016/j.lfs.2021.119730

    Article  CAS  PubMed  Google Scholar 

  9. Li H, Fan J, Zhao Y, Yang J, Xu H, Manthari RK, Cheng X, Wang J, Wang J (2021) Calcium alleviates fluoride-induced kidney damage via FAS/FASL, TNFR/TNF, DR5/TRAIL pathways in rats. Ecotoxicol Environ Saf 226:112851. https://doi.org/10.1016/j.ecoenv.2021.112851

    Article  CAS  PubMed  Google Scholar 

  10. Nanayakkara S, Senevirathna STMLD, Harada KH, Chandrajith R, Nanayakkara N, Koizumi A (2020) The influence of fluoride on chronic kidney disease of uncertain aetiology (CKDu) in Sri Lanka. Chemosphere 257:127186. https://doi.org/10.1016/j.chemosphere.2020.127186

    Article  CAS  PubMed  Google Scholar 

  11. Saylor C, Malin AJ, Tamayo-Ortiz M, Cantoral A, Amarasiriwardena C, Estrada-Gutierrez G, Tolentino MC, Pantic I, Wright RO, Tellez-Rojo MM, Sanders AP (2022) Early childhood fluoride exposure and preadolescent kidney function. Environ Res 204:112014. https://doi.org/10.1016/j.envres.2021.112014

    Article  CAS  PubMed  Google Scholar 

  12. Wu L, Fan C, Zhang Z, Zhang X, Lou Q, Guo N, Huang W, Zhang M, Yin F, Guan Z, Yang Y, Gao Y (2021) Association between fluoride exposure and kidney function in adults: a cross-sectional study based on endemic fluorosis area in China. Ecotoxicol Environ Saf 225:112735. https://doi.org/10.1016/j.ecoenv.2021.112735

    Article  CAS  PubMed  Google Scholar 

  13. Wei W, Pang S, Sun D (2019) The pathogenesis of endemic fluorosis: research progress in the last 5 years. J Cell Mol Med 23:2333–2342. https://doi.org/10.1111/jcmm.14185

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Waugh DT (2019) Fluoride exposure induces inhibition of sodium-and potassium-activated adenosine triphosphatase (Na+, K+-ATPase) enzyme activity: molecular mechanisms and implications for public health. Int J Environ Res Public Health 16:1427. https://doi.org/10.3390/ijerph16081427

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Unde MP, Patil RU, Dastoor PP (2018) The untold story of fluoridation: revisiting the changing perspectives. Indian J Occup Environ Med 22:121–127. https://doi.org/10.4103/ijoem.IJOEM_124_18

    Article  PubMed  PubMed Central  Google Scholar 

  16. Roman RJ, Carter JR, North WC, Kauker ML (1977) Renal tubular site of action of fluoride in fischer 344 rats. Anesthesiology 46:260–264. https://doi.org/10.1097/00000542-197704000-00006

    Article  CAS  PubMed  Google Scholar 

  17. Wang HW, Zhao WP, Liu J, Tan PP, Zhang C, Zhou BH (2017) Fluoride-induced oxidative stress and apoptosis are involved in the reducing of oocytes development potential in mice. Chemosphere 186:911–918. https://doi.org/10.1016/j.chemosphere.2017.08.068

    Article  CAS  PubMed  Google Scholar 

  18. Adedara IA, Ojuade TJD, Olabiyi BF, Idris UF, Onibiyo EM, Ajeigbe OF, Farombi EO (2017) Taurine ameliorates renal oxidative damage and thyroid dysfunction in rats chronically exposed to fluoride. Biol Trace Elem Res 175:388–395. https://doi.org/10.1007/s12011-016-0784-2

    Article  CAS  PubMed  Google Scholar 

  19. Sharma P, Verma PK, Sood S, Singh M, Verma D (2023) Impact of chronic sodium fluoride toxicity on antioxidant capacity, biochemical parameters, and histomorphology in cardiac, hepatic, and renal tissues of wistar rats. Biol Trace Elem Res 201:229–241. https://doi.org/10.1007/s12011-022-03113-w

    Article  CAS  PubMed  Google Scholar 

  20. Nabavi SF, Moghaddam AH, Eslami S, Nabavi SM (2012) Protective effects of curcumin against sodium fluoride-induced toxicity in rat kidneys. Biol Trace Elem Res 145:369–374. https://doi.org/10.1007/s12011-011-9194-7

    Article  CAS  PubMed  Google Scholar 

  21. Li H, Hao Z, Wang L, Yang J, Zhao Y, Cheng X, Yuan H, Wang J (2022) Dietary calcium alleviates fluorine-induced liver injury in rats by mitochondrial apoptosis pathway. Biol Trace Elem Res 200:271–280. https://doi.org/10.1007/s12011-021-02641-1

    Article  CAS  PubMed  Google Scholar 

  22. Kleele T, Rey T, Winter J, Zaganelli S, Mahecic D, Perreten Lambert H, Ruberto FP, Nemir M, Wai T, Pedrazzini T, Manley S (2021) Distinct fission signatures predict mitochondrial degradation or biogenesis. Nature 593:435–439. https://doi.org/10.1038/s41586-021-03510-6

    Article  CAS  PubMed  Google Scholar 

  23. Rovira-Llopis S, Bañuls C, Diaz-Morales N, Hernandez-Mijares A, Rocha M, Victor VM (2017) Mitochondrial dynamics in type 2 diabetes: pathophysiological implications. Redox Biol 11:637–645. https://doi.org/10.1016/j.redox.2017.01.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Cheng L, Yang X, Jian Y, Liu J, Ke X, Chen S, Yang D, Yang D (2022) SIRT3 deficiency exacerbates early-stage fibrosis after ischaemia-reperfusion-induced AKI. Cell Signal 93:110284. https://doi.org/10.1016/j.cellsig.2022.110284

    Article  CAS  PubMed  Google Scholar 

  25. Zhu Y, Wang D, Luo J, Jie J, Liu H, Peng L, Bai X, Li D (2022) Zingerone inhibits the neutrophil extracellular trap formation and protects against sepsis via Nrf2-Mediated ROS inhibition. Oxid Med Cell Longev 2022:1–16. https://doi.org/10.1155/2022/3990607

    Article  CAS  Google Scholar 

  26. Sharma P, Verma PK, Sood S, Yousuf R, Kumar A, Raina R, Shabbir MA, Bhat ZF (2023) Protective effect of quercetin and ginger (Zingiber officinale) extract against dimethoate potentiated fluoride-induced nephrotoxicity in rats. Foods 12:1899. https://doi.org/10.3390/foods12091899

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Dharmaratne R (2019) Exploring the role of excess fluoride in chronic kidney disease: a review. Hum Exp Toxicol 38:269–279. https://doi.org/10.1177/0960327118814161

    Article  CAS  PubMed  Google Scholar 

  28. Quadri JA, Sarwar S, Sinha A, Kalaivani M, Dinda AK, Bagga A, Roy TS, Das TK, Shariff A (2018) Fluoride-associated ultrastructural changes and apoptosis in human renal tubule: a pilot study. Hum Exp Toxicol 37:1199–1206. https://doi.org/10.1177/0960327118755257

    Article  CAS  PubMed  Google Scholar 

  29. Whitford G, Pashley D, Stringer G (1976) Fluoride renal clearance: a pH-dependent event. Am J Physiol-Legacy Content 230:527–532. https://doi.org/10.1152/ajplegacy.1976.230.2.527

    Article  CAS  Google Scholar 

  30. Murakami S, Funahashi K, Tamagawa N, Ning M, Ito T (2022) Taurine ameliorates streptozotocin-induced diabetes by modulating hepatic glucose metabolism and oxidative stress in mice. Metabolites 12:524. https://doi.org/10.3390/metabo12060524

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Prakash AR, Nahar P, Ashtekar M, Natarajan S, Singh R, Kulkarni G (2020) Detection of salivary alkaline phosphatase levels in smokers, diabetic patients, potentially malignant diseases and oral malignant tumours. J Pharm Bioallied Sci 12:S430–S435. https://doi.org/10.4103/jpbs.JPBS_129_20

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Dawson KJ (1996) Evolutionary consequences of a trade-off between parental effort and mating effort. J Theor Biol 183:139–158. https://doi.org/10.1006/jtbi.1996.0208

    Article  CAS  PubMed  Google Scholar 

  33. Silverman RC, Silverman A-J, Gibson MJ (1989) Identification of gonadotropin releasing hormone (GnRH) neurons projecting to the median eminence from third ventricular preoptic area grafts in hypogonadal mice. Brain Res 501:260–268. https://doi.org/10.1016/0006-8993(89)90643-4

    Article  CAS  PubMed  Google Scholar 

  34. Lisowska-Myjak B (2010) Serum and urinary biomarkers of acute kidney injury. Blood Purif 29:357–365. https://doi.org/10.1159/000309421

    Article  CAS  PubMed  Google Scholar 

  35. Rastogi R, Upreti RK, Kidwai AM (1987) Effect of fluoride on the intestinal epithelial cell brush border membrane. Bull Environ Contam Toxicol 39:162–167. https://doi.org/10.1007/BF01691805

    Article  CAS  PubMed  Google Scholar 

  36. Hu CY, Ren LQ, Li XN, Wu N, Li GS, Liu QY, Xu H (2012) Effect of fluoride on insulin level of rats and insulin receptor expression in the MC3T3-E1 cells. Biol Trace Elem Res 150:297–305. https://doi.org/10.1007/s12011-012-9482-x

    Article  CAS  PubMed  Google Scholar 

  37. Çetin S, Yur F (2016) Levels of trace elements in muscle and kidney tissues of sheep with fluorosis. Biol Trace Elem Res 174:82–84. https://doi.org/10.1007/s12011-016-0694-3

    Article  CAS  PubMed  Google Scholar 

  38. Han S, Lin F, Qi Y, Liu C, Zhou L, Xia Y, Chen K, Xing J, Liu Z, Yu W, Zhang Y, Zhou X, Rao T, Cheng F (2022) HO-1 contributes to luteolin-triggered ferroptosis in clear cell renal cell carcinoma via increasing the labile iron pool and promoting lipid peroxidation. Oxid Med Cell Longev 2022:1–26. https://doi.org/10.1155/2022/3846217

    Article  CAS  Google Scholar 

  39. Jiang B, Liu G, Zheng J, Chen M, Maimaitiming Z, Chen M, Liu S, Jiang R, Fuqua BK, Dunaief JL, Vulpe CD, Anderson GJ, Wang H, Chen H (2016) Hephaestin and ceruloplasmin facilitate iron metabolism in the mouse kidney. Sci Rep 6:39470. https://doi.org/10.1038/srep39470

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Maheshwari N, Qasim N, Anjum R, Mahmood R (2021) Fluoride enhances generation of reactive oxygen and nitrogen species, oxidizes hemoglobin, lowers antioxidant power and inhibits transmembrane electron transport in isolated human red blood cells. Ecotoxicol Environ Saf 208:111611. https://doi.org/10.1016/j.ecoenv.2020.111611

    Article  CAS  PubMed  Google Scholar 

  41. Ommati MM, Attari H, Siavashpour A, Shafaghat M, Azarpira N, Ghaffari H, Moezi L, Heidari R (2021) Mitigation of cholestasis-associated hepatic and renal injury by edaravone treatment: evaluation of its effects on oxidative stress and mitochondrial function. Liver Res 5:181–193. https://doi.org/10.1016/j.livres.2020.10.003

    Article  CAS  Google Scholar 

  42. Ommati MM, Mohammadi H, Mousavi K, Azarpira N, Farshad O, Dehghani R, Najibi A, Kamran S, Niknahad H, Heidari R (2021) Metformin alleviates cholestasis-associated nephropathy through regulating oxidative stress and mitochondrial function. Liver Res 5:171–180. https://doi.org/10.1016/j.livres.2020.12.001

    Article  CAS  Google Scholar 

  43. Heidari R, Behnamrad S, Khodami Z, Ommati MM, Azarpira N, Vazin A (2019) The nephroprotective properties of taurine in colistin-treated mice is mediated through the regulation of mitochondrial function and mitigation of oxidative stress. Biomed Pharmacother 109:103–111. https://doi.org/10.1016/j.biopha.2018.10.093

    Article  CAS  PubMed  Google Scholar 

  44. Sabouny R, Shutt TE (2020) Reciprocal regulation of mitochondrial fission and fusion. Trends Biochem Sci 45:564–577. https://doi.org/10.1016/j.tibs.2020.03.009

    Article  CAS  PubMed  Google Scholar 

  45. Qin L, Xi S (2022) The role of Mitochondrial fission proteins in mitochondrial dynamics in kidney disease. Int J Mol Sci 23:14725. https://doi.org/10.3390/ijms232314725

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Machiela E, Liontis T, Dues DJ, Rudich PD, Traa A, Wyman L, Kaufman C, Cooper JF, Lew L, Nadarajan S, Senchuk MM, Van Raamsdonk JM (2020) Disruption of mitochondrial dynamics increases stress resistance through activation of multiple stress response pathways. FASEB J 34:8475–8492. https://doi.org/10.1096/fj.201903235R

    Article  CAS  PubMed  Google Scholar 

  47. Tao Z, Xiao Q, Che X, Zhang H, Geng N, Shao Q (2022) Regulating mitochondrial homeostasis and inhibiting inflammatory responses through celastrol. Ann Transl Med 10:400. https://doi.org/10.21037/atm-21-7015

  48. S M, S K, E C, T von Z (2022) Mitochondrial dysfunction in cell senescence and aging. J Clin Investig 132. https://doi.org/10.1172/JCI158447

  49. Losón OC, Song Z, Chen H, Chan DC (2013) Fis1, Mff, MiD49, and MiD51 mediate Drp1 recruitment in mitochondrial fission. Mol Biol Cell 24:659–667. https://doi.org/10.1091/mbc.E12-10-0721

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Yi J, Liao J, Bai T, Wang B, Yangzom C, Ahmed Z, Mehmood K, Abbas RZ, Li Y, Tang Z, Zhang H (2022) Battery wastewater induces nephrotoxicity via disordering the mitochondrial dynamics. Chemosphere 303:135018. https://doi.org/10.1016/j.chemosphere.2022.135018

    Article  CAS  PubMed  Google Scholar 

  51. Wang S, Zhu H, Li R, Mui D, Toan S, Chang X, Zhou H (2022) DNA-PKcs interacts with and phosphorylates Fis1 to induce mitochondrial fragmentation in tubular cells during acute kidney injury. Sci Signal 15:eabh1121. https://doi.org/10.1126/scisignal.abh1121

  52. Palmer CS, Elgass KD, Parton RG, Osellame LD, Stojanovski D, Ryan MT (2013) Adaptor proteins MiD49 and MiD51 can act independently of Mff and Fis1 in Drp1 recruitment and are specific for mitochondrial fission. J Biol Chem 288:27584–27593. https://doi.org/10.1074/jbc.M113.479873

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Zhou BH, Wei SS, Jia LS, Zhang Y, Miao CY, Wang HW (2020) Drp1/Mff signaling pathway is involved in fluoride-induced abnormal fission of hepatocyte mitochondria in mice. Sci Total Environ 725:138192. https://doi.org/10.1016/j.scitotenv.2020.138192

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported by the National Natural Science Foundation of China (Grant No.·32102740).

Author information

Authors and Affiliations

  1. Henan Key Laboratory of Environmental and Animal Product Safety, Henan University of Science and Technology, Kaiyuan Avenue 263, Luoyang, 471000, Henan, People’s Republic of China

    Qiyong Zuo, Lin Lin, Yuling Zhang, Mohammad Mehdi Ommati, Hongwei Wang & Jing Zhao

Authors
  1. Qiyong Zuo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lin Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yuling Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mohammad Mehdi Ommati
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hongwei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jing Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Qiyong Zuo: Formal analysis, writing the original draft, preparation of the data presentation. Lin Lin: Visualization, validation, data curation. Yuling Zhang: Validation, project administration. Mohammad Mehdi Ommati: Ideas, investigation, critical review. Hongwei Wang: Conceptualization, methodology, review and editing, provision of resources. Jing Zhao: Funding acquisition, validation.

Corresponding author

Correspondence to Jing Zhao.

Ethics declarations

Ethics Approval

The experimental design was approved by the Institutional Animal Experiment Committee of Henan University of Science and Technology, China.

Consent to Participate

Written informed consent for publication was obtained from all participants.

Consent for Publication

Written informed consent for publication was obtained from all participants.

Competing Interests

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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

Zuo, Q., Lin, L., Zhang, Y. et al. The Footprints of Mitochondrial Fission and Apoptosis in Fluoride-Induced Renal Dysfunction. Biol Trace Elem Res (2023). https://doi.org/10.1007/s12011-023-03994-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12011-023-03994-5

Keywords

Search

Navigation