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International Urology and Nephrology

, Volume 48, Issue 3, pp 441–450 | Cite as

The effects of ozone therapy on caspase pathways, TNF-α, and HIF-1α in diabetic nephropathy

  • Aydın GüçlüEmail author
  • Haydar Ali Erken
  • Gülten Erken
  • Yavuz Dodurga
  • Arzu Yay
  • Özge Özçoban
  • Hasan Şimşek
  • Aydın Akçılar
  • Fatma Emel Koçak
Nephrology - Original Paper

Abstract

Background

Accelerated apoptosis plays a vital role in the development of diabetic vascular complications. Ozone may attenuate diabetic nephropathy by means of decreased apoptosis-related genes. The aim of our study was to investigate the effect of ozone therapy on streptozotocin-induced diabetic nephropathy in rats. Also the histopathological changes in diabetic kidney tissue with ozone treatment were evaluated.

Methods

The rats were randomly divided into six groups (n = 7): control (C), ozone (O), diabetic (D), ozone-treated diabetic (DO), insulin-treated diabetic (DI), and ozone- and insulin-treated diabetic (DOI). D, DI, and DOI groups were induced by a single intraperitoneal injection of streptozotocin. Ozone was given to the O, DO, and DOI groups. Group DI and DOI received subcutaneous (SC) insulin (3 IU). All animals received daily treatment for 6 weeks.

Results

Expressions of caspase-1-3-9, HIF-1α, and TNF-α genes were significantly higher in D group compared to C group (p < 0.05 for all). Ozone treatment resulted in significant decrease in the expressions of these genes in diabetic kidney tissue compared to both C and D group (p < 0.05 for all). Caspase-1-3-9, HIF-1α, and TNF-α gene expressions were found to be lower in DOI group compared to C group (p < 0.05 for all). Also adding ozone treatment to insulin therapy resulted in more significantly decrease in the expressions of these genes in diabetic tissue compared to only insulin-treated diabetic group (p < 0.05 for all). Regarding histological changes, ozone treatment resulted in decrease in the renal corpuscular inflammation and normal kidney morphology was observed. Both insulin and ozone therapies apparently improved kidney histological findings with less degenerated tubules and less inflammation of renal corpuscle compared to D, DO, and DI groups.

Conclusion

Ozone therapy decreases the expressions of apoptotic genes in diabetic kidney tissue and improves the histopathological changes.

Keywords

Diabetic nephropathy Ozone therapy Caspase HIF-1α TNF-α 

Notes

Compliance with ethical standards

Conflict of interest

None.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All experimental protocols conducted on the animals were consistent with the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals (NIH Publication No: 85-23) and approved by the Local Ethical Committee.

References

  1. 1.
    Alberti KGMM, Aschner P, Benet PH (1999) Definition, diagnosis and classification of diabetes mellitus and its complications. Report of WHO consultation. Geneva: World Health Organization: part 1; 2–3Google Scholar
  2. 2.
    Tuttle KR (2005) Linking metabolism and immunology: diabetic nephropathy is an inflammatory disease. J Am Soc Nephrol 16:1537–1538CrossRefPubMedGoogle Scholar
  3. 3.
    Mora C, Navarro JF (2006) Inflammation and diabetic nephropathy. Curr Diabetes Rep 6:463–468CrossRefGoogle Scholar
  4. 4.
    Su J, Zhou L, Kong X, Yang X, Xiang X, Zhang Y, Li X, Sun L (2013) Endoplasmic reticulum is at the crossroads of autophagy, inflammation, and apoptosis signaling pathways and participates in the pathogenesis of diabetes mellitus. J Diabetes Res. doi: 10.1155/2013/193461 Google Scholar
  5. 5.
    Okouchi M, Okayama N, Aw TY (2009) Preservation of cellular glutathione status and mitochondrial membrane potential by N-acetylcysteine and insulin sensitizers prevent carbonyl stress-induced human brain endothelial cell apoptosis. Curr Neurovasc Res 6:267–278PubMedCentralCrossRefPubMedGoogle Scholar
  6. 6.
    Cai L, Li W, Wang G, Guo L, Jiang Y, Kang YJ (2002) Hyperglycemia-induced apoptosis in mouse myocardium—mitochondrial cytochrome c-mediated caspase-3 activation pathway. Diabetes 51:1938–1948CrossRefPubMedGoogle Scholar
  7. 7.
    Romeo G, Liu WH, Asnaghi V, Kern TS, Lorenzi M (2002) Activation of nuclear factor-kappa B induced by diabetes and high glucose regulates a proapoptotic program in retinal pericytes. Diabetes 51:2241–2248CrossRefPubMedGoogle Scholar
  8. 8.
    Ortiz A, Ziyadeh FN (1997) Expression of apoptosis-regulatory genes in renal proximal tubular epithelial cells exposed to high ambient glucose and in diabetic kidneys. J Investig Med 45:50–56PubMedGoogle Scholar
  9. 9.
    Wolf G, Chen S, Ziyadeh FN (2005) From the periphery of the glomerular capillary wall toward the center of disease. Diabetes 54:1626–1634CrossRefPubMedGoogle Scholar
  10. 10.
    Allen DA, Harwood S, Varagunam M, Raftery MJ, Yaqoob MM (2003) High-glucose-induced oxidative stress causes apoptosis in proximal tubular epithelial cells and is mediated by multiple caspases. FASEB J 17:908–910PubMedGoogle Scholar
  11. 11.
    Wei Z, Ning NL, Jian HX, Zhe LL (2009) HIF-1α expression and retinal cell apoptosis in rat retina ischemia-reperfusion injury. Int J Ophthalmol 2:227–230Google Scholar
  12. 12.
    Cao ZH, Zheng QY, Li GQ, Hu XB, Feng SL, Xu GL, Zhang KQ (2015) STAT1-mediated down-regulation of bcl-2 expression is involved in IFN-γ/TNF-α-induced apoptosis in NIT-1 Cells. PLoS One 10. doi: 10.1371/journal.pone.0120921
  13. 13.
    Sagar SK, Zhang C, Guo Q, Yi R, Tang L (2013) Role of expression of endothelin-1 and angiotensin-II and hypoxia-inducible factor-1α in the kidney tissues of patients with diabetic nephropathy. Saudi J Kidney Dis Transpl 24:959–964CrossRefPubMedGoogle Scholar
  14. 14.
    Tang L, Yi R, Yang B, Li H, Chen H, Liu Z (2012) Valsartan inhibited HIF-1α pathway and attenuated renal interstitial fibrosis in streptozotocin-diabetic rats. Diabetes Res Clin Pract 97:125–131CrossRefPubMedGoogle Scholar
  15. 15.
    Chung CH, Fan J, Lee EY, Kang JS, Lee SJ, Pyagay PE, Khoury CC, Yeo TK, Khayat MF, Wang A, Chen S (2015) Effects of tumor necrosis factor-α on podocyte expression of monocyte chemoattractant protein-1 and in diabetic nephropathy. Nephron Extra 5:1–18PubMedCentralCrossRefPubMedGoogle Scholar
  16. 16.
    Fuccio C, Luongo C, Capodanno P, Giordano C, Scafuro MA, Siniscalco D, Lettieri B, Rossi F, Maione S, Berrino L (2009) A single subcutaneous injection of ozone prevents allodynia and decreases the over-expression of pro-inflammatory caspases in the orbito-frontal cortex of neuropathic mice. Eur J Pharmacol 603:42–49CrossRefPubMedGoogle Scholar
  17. 17.
    Haj B, Sukhotnik I, Shaoul R, Pollak Y, Coran AG, Bitterman A, Matter I (2014) Effect of ozone on intestinal recovery following intestinal ischemia-reperfusion injury in a rat. Pediatr Surg Int 30:181–188CrossRefPubMedGoogle Scholar
  18. 18.
    Morsy MD, Hassan WN, Zalat SI (2010) Improvement of renal oxidative stress markers after ozone administration in diabetic nephropathy in rats. Diabetol Metab Syndr. doi: 10.1186/1758-5996-2-29 PubMedCentralPubMedGoogle Scholar
  19. 19.
    Erken HA, Genç O, Erken G, Ayada C, Gündoğdu G, Doğan H (2015) Ozone partially prevents diabetic neuropathy in rats. Exp Clin Endocrinol Diabetes 2:101–105Google Scholar
  20. 20.
    León OS, Menéndez S, Merino N, Castillo R, Sam S, Pérez L, Cruz E, Bocci V (1998) Ozone oxidative preconditioning: a protection against cellular damage by free radicals. Mediators Inflamm 7:289–294PubMedCentralCrossRefPubMedGoogle Scholar
  21. 21.
    Yay A, Akkuş D, Yapıslar H, Balcıoglu E, Sonmez MF, Ozdamar S (2014) Antioxidant effect of carnosine treatment on renal oxidative stress in streptozotocin-induced diabetic rats. Biotech Histochem 89:552–557CrossRefPubMedGoogle Scholar
  22. 22.
    Kumar D, Zimpelmann J, Robertson S, Burns KD (2004) Tubular and interstitial cell apoptosis in the streptozotocin-diabetic rat kidney. Nephron Exp Nephrol 96:77–88CrossRefGoogle Scholar
  23. 23.
    Wong VY, Keller PM, Nuttall ME, Kikly K, De Wolf WE Jr, Lee D, Ali SM, Nadeau DP, Grygielko ET, Laping NJ, Brooks DP (2001) Role of caspases in human renal proximal tubular epithelial cell apoptosis. Eur J Pharm 433:135–140CrossRefGoogle Scholar
  24. 24.
    Liadis N, Murakami K, Eweida M, Elford AR, Sheu L, Gaisano HY, Hakem R, Ohashi PS, Woo M (2005) Caspase-3-dependent β-cell apoptosis in the initiation of autoimmune diabetes mellitus. Mol Cell Bioe 25:3620–3629CrossRefGoogle Scholar
  25. 25.
    Ho FM, Liu SH, Liau CS, Huang PJ, Lin-Shiau SY (2000) High glucose-induced apoptosis in human endothelial cells is mediated by sequential activations of c-Jun NH(2)-terminal kinase and caspase-3. Circulation 101:2618–2624CrossRefPubMedGoogle Scholar
  26. 26.
    Koenen TB, Stienstra R, van Tits LJ, de Graaf J, Stalenhoef AF, Joosten LA, Tack CJ, Netea MG (2011) Hyperglycemia activates caspase-1 and TXNIP-mediated IL-1b transcription in human adipose tissue. Diabetes 60:517–552PubMedCentralCrossRefPubMedGoogle Scholar
  27. 27.
    Güçlü A, Yonguç N, Dodurga Y, Gündoğdu G, Güçlü Z, Yonguç T, Adıgüzel E, Turkmen K (2015) The effects of grape seed on apoptosis-related gene expression and oxidative stress in streptozotocin-induced diabetic rats. Ren Fail 37:192–197CrossRefPubMedGoogle Scholar
  28. 28.
    Peralta C, León OS, Xaus C, Prats N, Jalil EC, Planell ES, Puig-Parellada P, Gelpí E, Roselló-Catafau J (1999) Protective effect of ozone treatment on the injury associated with hepatic ischemia-reperfusion: antioxidant-prooxidant balance. Free Radic Res 31:191–196CrossRefPubMedGoogle Scholar
  29. 29.
    Al-Dalain SM, Martínez G, Candelario-Jalil E, Menéndez S, Re L, Giuliani A, León OS (2001) Ozone treatment reduces markers of oxidative and endothelial damage in an experimental diabetes model in rats. Pharmacol Res 44:391–396CrossRefPubMedGoogle Scholar
  30. 30.
    Martínez-Sánchez G, Al-Dalain SM, Menéndez S, Re L, Giuliani A, Candelario-Jalil E, Alvarez H, Fernández-Montequín JI, León OS (2005) Therapeutic efficacy of ozone in patients with diabetic foot. Eur J Pharmacol 523:151–161CrossRefPubMedGoogle Scholar
  31. 31.
    Candelario-Jalil E, Mohammed-Al-Dalain S, Fernández OS, Menéndez S, Pérez-Davison G, Merino N, Sam S, Ajamieh HH (2001) Oxidative preconditioning affords protection against carbon tetrachloride induced glycogen depletion and oxidative stress in rats. J Appl Toxicol 21:297–301CrossRefPubMedGoogle Scholar
  32. 32.
    Kawata K, Iwai A, Muramatsu D (2015) Stimulation of macrophages with the β-glucan produced by aureobasidium pullulans promotes the secretion of tumor necrosis factor-related apoptosis inducing ligand (TRAIL). PLoS One 4. doi: 10.1371/journal.pone.0124809
  33. 33.
    Xing B, Chen H, Wang L (2015) Ozone oxidative preconditioning protects the rat kidney from reperfusion injury via modulation of the TLR4-NF-κB pathway. Acta Cir Bras 30:60–66CrossRefPubMedGoogle Scholar
  34. 34.
    Azuma K, Mori T, Kawamoto K, Kuroda K, Tsuka T, Imagawa T, Osaki T, Itoh F, Minami S, Okamoto Y (2014) Anti-inflammatory effects of ozonated water in an experimental mouse model. Biomed Rep 2:671–674PubMedCentralPubMedGoogle Scholar
  35. 35.
    Carmeliet P, Dor Y, Herbert JM, Fukumura D, Brusselmans K, Dewerchin M, Neeman M, Bono F, Abramovitch R, Maxwell P, Koch CJ, Ratcliffe P, Moons L, Jain RK, Collen D, Keshert E (1998) Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature 394:485–490CrossRefPubMedGoogle Scholar
  36. 36.
    Sun HK, Lee YM, Han KH, Kim HS, Ahn SH, Han SY (2012) Phosphodiesterase inhibitor improves renal tubulointerstitial hypoxia of the diabetic rat kidney. Korean J Intern Med 27:163–170PubMedCentralCrossRefPubMedGoogle Scholar
  37. 37.
    Roy S, Sannigrahi S, Majumdar S, Ghosh B, Sarkar B (2011) Resveratrol regulates antioxidant status, inhibits cytokine expression and restricts apoptosis in carbon tetrachloride induced rat hepatic injury. Oxid Med Cell Longev. doi: 10.1155/703676 Google Scholar
  38. 38.
    Kumar B, Gupta SK, Nag TC, Srivastava S, Saxena R, Jha KA, Srinivasan BP (2014) Retinal neuroprotective effects of quercetin in streptozotocin-induced diabetic rats. Exp Eye Res 125:193–202CrossRefPubMedGoogle Scholar
  39. 39.
    Suzuki H, Tomida A, Tsuruo T (2001) Dephosphorylated hypoxia inducible factor 1 alpha as a mediator of p53-dependent apoptosis during hypoxia. Oncogene 20:5779–5788CrossRefPubMedGoogle Scholar
  40. 40.
    Chang Y, Hsiao G, Chen YC (2007) Tetramethylpyrazine suppresses HIF-1α, TNF-α, and activated caspase-3 expression in middle cerebral artery occlusion-induced brain ischemia in rats. Acta Pharmacol Sin 28:327–333CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2015

Authors and Affiliations

  • Aydın Güçlü
    • 1
    Email author
  • Haydar Ali Erken
    • 2
  • Gülten Erken
    • 2
  • Yavuz Dodurga
    • 3
  • Arzu Yay
    • 4
  • Özge Özçoban
    • 4
  • Hasan Şimşek
    • 5
  • Aydın Akçılar
    • 6
  • Fatma Emel Koçak
    • 7
  1. 1.Department of Nephrology, Faculty of MedicineAhi Evran UniversityKırşehirTurkey
  2. 2.Department of Physiology, Faculty of MedicineBalikesir UniversityBalikesirTurkey
  3. 3.Department of Medical BiologyPamukkale University School of MedicineDenizliTurkey
  4. 4.Department of Histology and EmbryologyErciyes University School of MedicineKayseriTurkey
  5. 5.Department of Physiology, Faculty of MedicineDumlupınar UniversityKutahyaTurkey
  6. 6.Experimental Research Unit, Faculty of MedicineDumlupınar UniversityKutahyaTurkey
  7. 7.Department of Biochemistry, Faculty of MedicineDumlupınar UniversityKutahyaTurkey

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