Öz
Amaç: Hipertansiyon, son dönem böbrek hastalığına ulaşan hastaların yaklaşık %30'undan sorumludur. Statin tedavisinin böbrek hastalığı gelişme riskini azalttığı bilinmektedir. Bu çalışmada, L-arginin analoğu N-Nitro-L-Arjinin Metil Ester (L-NAME) kullanılarak hipertansiyon oluşturulmuş sıçanların böbrek dokusunda kaspaz-3 ve fibrillin1 (FBN1) üzerindeki değişikliklere bakılarak, hipertansiyonun bu moleküller üzerinde oluşturduğu değişiklikleri rosuvastatinin ne şekilde etkilediği araştırıldı.
Araçlar ve Yöntem: Çalışmada, 200-220 g ağırlığında 18 adet Wistar Albino erkek sıçan kullanıldı. Sıçanlar her grupta 6 hayvan olacak şekilde 3 gruba ayrıldı (1.Kontrol, 2.Hipertansiyon, 3.Rosuvatatin). Hipertansiyon oluşturmak için sıçanlara 7 hafta boyunca nitrik oksit sentaz (NOS) inhibitörü L-NAME içme suyuna karıştırılarak verildi. İkinci hafta sonrasında rosuvastatin (10 mg/kg/gün) 5 hafta boyunca oral gavaj ile verildi. Kan basıncı değerleri 0, 14, 28 ve 42. günlerde tail-cuff yöntemi kullanılarak değerlendirildi. Deney bitiminde tüm sıçanlar dekapite edilerek böbrek dokularında kaspaz-3 ve FBN1 düzeyleri immunohistokimyasal yöntemle değerlendirildi.
Bulgular: Kan basınçları hipertansiyon grubunda kontrolle kıyaslandığında 14, 28, 42. günlerde anlamlı düzeyde yüksek bulundu (p=0.001). Rosuvastatin 28. ve 42. günde anlamlı olmayan bir azalmaya sebep oldu. Kontrol grubuyla kıyaslandığında hipertansiyon grubunda kaspaz-3 (p=0.001) ve FBN1 (p=0.001) immünreaktivitesinin istatistiksel düzeyde anlamlı bir seviyede arttığı görüldü. Hipertansiyon grubu ile kıyaslandığında rosuvastatin verilen grupta ise, kaspaz-3 (p=0.031) ve FBN1 (p=0.030) immünreaktivitesi anlamlı azaldı. Ancak, kontrol grubuna göre rosuvastatin grubunda kaspaz-3 (p=0.036) ve FBN1 (p=0.041) immünreaktivitesinin arttığı izlendi.
Sonuç: Rosuvastatin kan basınçlarını anlamlı olarak düşürmese de, hipertansif böbrekler üzerine koruyucu etkisinde kaspaz-3 ve FBN1’in aracı olabileceği düşünülmektedir.
Anahtar Kelimeler
Kaynakça
- 1. Rauch U, Osende JI, Chesebro JH, et al. Statins and cardiovascular diseases: the multiple effects of lipid-lowering therapy by statins. Atherosclerosis. 2000;153(1):181-189.
- 2. Suh JW, Choi DJ, Chang HJ, et al. HMG-CoA reductase inhibitor improves endothelial dysfunction in spontaneous hypertensive rats via down-regulation of caveolin-1 and activation of endothelial nitric oxide synthase. J Korean Med Sci. 2010;25(1):16-23.
- 3. Launer LJ, Masaki K, Petrovitch H, Foley D, Havlik RJ. The association between midlife blood pressure levels and late-life cognitive function. The Honolulu-Asia Aging Study. Jama. 1995;274(23):1846-1851.
- 4. Kotchen TA, Cowley AW Jr, Liang M. Ushering hypertension into a new era of precision medicine. Jama. 2016;315(4):343-344.
- 5. Eirin A, Lerman LO. Darkness at the end of the tunnel: Poststenotic kidney injury. Physiology (Bethesda). 2013;28(4):245-253.
- 6. Collins AJ, Foley RN, Chavers B, et al. Us renal data system annual data report. Am J Kidney Dis. 2013;61(1):e1–e480.
- 7. Bidani AK, Griffin KA. Pathophysiology of hypertensive renal damage: Implications for therapy. Hypertension. 2004;44(5):595-601.
- 8. Ramirez F, Pereira L. Mutations of extracellular matrix components in vascular disease. Ann Thorac Surg. 1999;67(6):1857-1858.
- 9. Kielty CM, Sherratt MJ, Shuttleworth CA. Elastic fibres. J Cell Sci. 2002;115(14):2817-2828.
- 10. Sherratt MJ, Wess TJ, Baldock C, et al. Fibrillin-rich microfibrils of the extracellular matrix: ultrastructure and assembly. Micron. 2001;32(2):185-200.
- 11. Ilhan S, Oktar S, Sahna E, Aksulu HE. Salt and nitric oxide inhibition induced hypertension: the role of prostacycline and 8-isoprostane. Clin Exp Hypertens. 2011;33(2):84-88.
- 12. Kunduzova OR, Escourrou G, Seguelas MH, et al. Prevention of apoptotic and necrotic cell death, caspase-3 activation, and renal dysfunction by melatonin after ischemia/reperfusion. FASEB J. 2003;17(8):872-874.
- 13. Mutlu E, Ilhan S, Onat E, Kara M, Sahna E. The effects of novokinin, AT2 agonist, on blood pressure, vascular responses, levels of ADMA, NADPH Oxidase and Rho Kinase in hypertension induced by NOS inhibition and salt. Turkish J Med Sci. 2016;46(4):1249-1257.
- 14. Neto-Ferreira R, Novaes Rocha V, da Silva Torres T, Mandarim-de-Lacerda CA, de Carvalho JJ. Beneficial effects of rosuvastatin on aortic adverse remodeling in nitric oxide-deficient rats. Exp Toxicol Pathol. 2011;63(5):473-478.
- 15. Susic D, Varagic J, Ahn J, Slama M, Frohlich ED. Beneficial pleiotropic vascular effects of rosuvastatin in two hypertensive models. J Am Coll Cardiol. 2003;42(6):1091-1097.
- 16. Sicard P, Lauzier B, Oudot A, et al. A treatment with rosuvastatin induced a reduction of arterial pressure and a decrease of oxidative stress in spontaneously hypertensive rats. Arch Mal Coeur Vaiss. 2005;98(2):804-808.
- 17. Hsu SM, Raine L, Fanger H. Use of avidin-biotin-peroxidase complex (ABC) in immunoperoxidase techniques: a comparison between ABC and unlabeled antibody (PAP) procedures. J Histochem Cytochem. 1981;29(4):577-580.
- 18. Gurel A, Aydin H, Yalcin A, et al. Cinnamon Protects Kidneys Against Doxorubicin-Induced Nephrotoxicity. Anal Quant Cytopathol Hıstpathol. 2022;43(5):311-319.
- 19. Zatz R, Baylis C. Chronic nitric oxide inhibition model six years on. Hypertension. 1998;32(6):958-964.
- 20. Gardiner SM, Kemp PA, Bennett T, Palmer RM, Moncada S. Nitric oxide synthase inhibitors cause sustained, but reversible, hypertension and hindquarters vasoconstriction in Brattleboro rats. Eur J Pharmacol. 1992;213(3):449-451.
- 21. Sinaiko AR, Steinberger J, Moran A, et al. Relation of body mass index and insulin resistance to cardiovascular risk factors, inflammatory factors, and oxidative stress during adolescence. Circulation. 2005;111(15):1985-1991.
- 22. Krepela E. Cysteine proteinases in tumor cell growth and apoptosis. Neoplasma.2001;48(5):332-349.
- 23. Sanz AB, Santamaria B, Ruiz-Ortega M, Egido J, Ortiz A. Mechanisms of renal apoptosis in health and disease. JASN. 2008;19(9):1634-1642.
- 24. Ying WZ, Sanders PW. Cytochrome c mediates apoptosis in hypertensive nephrosclerosis in dahl/rapp rats. Kidney Int. 2001;59(2):662-672.
- 25. Qingbo Lv, Wang Y, Li Y, et al. Rosuvastatin Reverses Hypertension-Induced Changes in the Aorta Structure and Endothelium-Dependent Relaxation in Rats Through Suppression of Apoptosis and Inflammation. J Cardiovasc Pharmacol. 2020;75(6): 584-595.
- 26. Arama E, Agapite J, Steller H. Caspase activity and a specific cytochrome C are required for sperm differentiation in Drosophila. Dev Cell. 2003;4(5): 687-697.
- 27. Walsh K, Smith RC, Kim HS. Vascular cell apoptosis in remodeling, restenosis, and plaque rupture. Circ Res. 2000;87(3):184-188.
- 28. Sakai LY, Keene DR, Engvall E. Fibrillin, a new 350-kD glycoprotein, is a component of extracellular microfibrils. J. Cell Biol. 1986;103:2499-2509.
Öz
Purpose: Hypertension is responsible for approximately 30% of patients who reach end-stage renal disease. Statin is known to reduce the risk of developing kidney disease. In this study, the changes in caspase-3 and fibrillin1 in the kidney tissue of rats with hypertension using L-NAME were investigated along with how rosuvastatin affected the changes caused by hypertension on these proteins.
Materials and Methods: 18 Wistar Albino male rats weighing 200-220 g were used in the study. The rats were divided into 3 groups with 6 animals in each group (1.Control, 2.Hypertension, 3.Rosuvastatin).To induce hypertension, rats were given L-NAME for 7 weeks. After the second week, rosuvastatin was given by oral gavage for 5 weeks. Blood pressure values were evaluated on days 0, 14, 28, 42. At the end of the experiment, all rats were sacrificed and caspase-3 and fibrillin1 levels were evaluated.
Results: Blood pressures were found to be higher in the hypertension group on the 14th, 28th, and 42nd days (p=0.001). Rosuvastatin caused a decrease that was found to be insignificant at 28th, 42nd days. Caspase-3 (p=0.001), fibrillin1 (p=0.001) immunoreactivity were found to be increased in the hypertension group. Compared with the hypertension group, caspase-3 (p=0.031), fibrillin1 (p=0.030) immunoreactivity were decreased in the rosuvastatin group. However, caspase-3 (p=0.036) and fibrillin1 (p=0.041) immunoreactivity was increased in the rosuvastatin group compared to the control group.
Conclusion: Although rosuvastatin didn’t significantly decrease blood pressure, it is thought that caspase-3 and fibrillin1 may mediate its protective effect on hypertensive kidneys.
Anahtar Kelimeler
Kaynakça
- 1. Rauch U, Osende JI, Chesebro JH, et al. Statins and cardiovascular diseases: the multiple effects of lipid-lowering therapy by statins. Atherosclerosis. 2000;153(1):181-189.
- 2. Suh JW, Choi DJ, Chang HJ, et al. HMG-CoA reductase inhibitor improves endothelial dysfunction in spontaneous hypertensive rats via down-regulation of caveolin-1 and activation of endothelial nitric oxide synthase. J Korean Med Sci. 2010;25(1):16-23.
- 3. Launer LJ, Masaki K, Petrovitch H, Foley D, Havlik RJ. The association between midlife blood pressure levels and late-life cognitive function. The Honolulu-Asia Aging Study. Jama. 1995;274(23):1846-1851.
- 4. Kotchen TA, Cowley AW Jr, Liang M. Ushering hypertension into a new era of precision medicine. Jama. 2016;315(4):343-344.
- 5. Eirin A, Lerman LO. Darkness at the end of the tunnel: Poststenotic kidney injury. Physiology (Bethesda). 2013;28(4):245-253.
- 6. Collins AJ, Foley RN, Chavers B, et al. Us renal data system annual data report. Am J Kidney Dis. 2013;61(1):e1–e480.
- 7. Bidani AK, Griffin KA. Pathophysiology of hypertensive renal damage: Implications for therapy. Hypertension. 2004;44(5):595-601.
- 8. Ramirez F, Pereira L. Mutations of extracellular matrix components in vascular disease. Ann Thorac Surg. 1999;67(6):1857-1858.
- 9. Kielty CM, Sherratt MJ, Shuttleworth CA. Elastic fibres. J Cell Sci. 2002;115(14):2817-2828.
- 10. Sherratt MJ, Wess TJ, Baldock C, et al. Fibrillin-rich microfibrils of the extracellular matrix: ultrastructure and assembly. Micron. 2001;32(2):185-200.
- 11. Ilhan S, Oktar S, Sahna E, Aksulu HE. Salt and nitric oxide inhibition induced hypertension: the role of prostacycline and 8-isoprostane. Clin Exp Hypertens. 2011;33(2):84-88.
- 12. Kunduzova OR, Escourrou G, Seguelas MH, et al. Prevention of apoptotic and necrotic cell death, caspase-3 activation, and renal dysfunction by melatonin after ischemia/reperfusion. FASEB J. 2003;17(8):872-874.
- 13. Mutlu E, Ilhan S, Onat E, Kara M, Sahna E. The effects of novokinin, AT2 agonist, on blood pressure, vascular responses, levels of ADMA, NADPH Oxidase and Rho Kinase in hypertension induced by NOS inhibition and salt. Turkish J Med Sci. 2016;46(4):1249-1257.
- 14. Neto-Ferreira R, Novaes Rocha V, da Silva Torres T, Mandarim-de-Lacerda CA, de Carvalho JJ. Beneficial effects of rosuvastatin on aortic adverse remodeling in nitric oxide-deficient rats. Exp Toxicol Pathol. 2011;63(5):473-478.
- 15. Susic D, Varagic J, Ahn J, Slama M, Frohlich ED. Beneficial pleiotropic vascular effects of rosuvastatin in two hypertensive models. J Am Coll Cardiol. 2003;42(6):1091-1097.
- 16. Sicard P, Lauzier B, Oudot A, et al. A treatment with rosuvastatin induced a reduction of arterial pressure and a decrease of oxidative stress in spontaneously hypertensive rats. Arch Mal Coeur Vaiss. 2005;98(2):804-808.
- 17. Hsu SM, Raine L, Fanger H. Use of avidin-biotin-peroxidase complex (ABC) in immunoperoxidase techniques: a comparison between ABC and unlabeled antibody (PAP) procedures. J Histochem Cytochem. 1981;29(4):577-580.
- 18. Gurel A, Aydin H, Yalcin A, et al. Cinnamon Protects Kidneys Against Doxorubicin-Induced Nephrotoxicity. Anal Quant Cytopathol Hıstpathol. 2022;43(5):311-319.
- 19. Zatz R, Baylis C. Chronic nitric oxide inhibition model six years on. Hypertension. 1998;32(6):958-964.
- 20. Gardiner SM, Kemp PA, Bennett T, Palmer RM, Moncada S. Nitric oxide synthase inhibitors cause sustained, but reversible, hypertension and hindquarters vasoconstriction in Brattleboro rats. Eur J Pharmacol. 1992;213(3):449-451.
- 21. Sinaiko AR, Steinberger J, Moran A, et al. Relation of body mass index and insulin resistance to cardiovascular risk factors, inflammatory factors, and oxidative stress during adolescence. Circulation. 2005;111(15):1985-1991.
- 22. Krepela E. Cysteine proteinases in tumor cell growth and apoptosis. Neoplasma.2001;48(5):332-349.
- 23. Sanz AB, Santamaria B, Ruiz-Ortega M, Egido J, Ortiz A. Mechanisms of renal apoptosis in health and disease. JASN. 2008;19(9):1634-1642.
- 24. Ying WZ, Sanders PW. Cytochrome c mediates apoptosis in hypertensive nephrosclerosis in dahl/rapp rats. Kidney Int. 2001;59(2):662-672.
- 25. Qingbo Lv, Wang Y, Li Y, et al. Rosuvastatin Reverses Hypertension-Induced Changes in the Aorta Structure and Endothelium-Dependent Relaxation in Rats Through Suppression of Apoptosis and Inflammation. J Cardiovasc Pharmacol. 2020;75(6): 584-595.
- 26. Arama E, Agapite J, Steller H. Caspase activity and a specific cytochrome C are required for sperm differentiation in Drosophila. Dev Cell. 2003;4(5): 687-697.
- 27. Walsh K, Smith RC, Kim HS. Vascular cell apoptosis in remodeling, restenosis, and plaque rupture. Circ Res. 2000;87(3):184-188.
- 28. Sakai LY, Keene DR, Engvall E. Fibrillin, a new 350-kD glycoprotein, is a component of extracellular microfibrils. J. Cell Biol. 1986;103:2499-2509.
Ayrıntılar
| Birincil Dil | İngilizce |
|---|---|
| Konular | Klinik Tıp Bilimleri, Klinik Tıp Bilimleri (Diğer) |
| Bölüm | Bilimsel Araştırma Makaleleri |
| Yazarlar | |
| Erken Görünüm Tarihi | 5 Temmuz 2023 |
| Yayımlanma Tarihi | 7 Ağustos 2023 |
| Yayımlandığı Sayı | Yıl 2023 Cilt: 7 Sayı: 2 |
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