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Histomorphological Changes of Apelin Treatment in Renal Tissue in Doxorubicin-induced Nephrotic Syndrome Model

Year 2016, Volume: 6 Issue: 1, 20 - 27, 13.05.2016

Abstract

Objective: Nephrotic syndrome (NS) may result in renal failure. Apelin (AP), a vasoactive peptide, demonstrates its effect by binding to the AP receptor. AP, present in the endothelial and vascular smooth muscle cells of glomerular arterioles, affects the pre- and post-microvascularization by regulating renal hemodynamics. This study aimed to determine the histomorphological changes of AP treatment in a doxorubicin (DOX)-induced NS model.

Methods: Male Sprague Dawley rats were used. Rats were randomly divided into four groups (n=6): control [physiological saline (PS) solution intraperitoneal (i.p.)]; AP+PS (PS and 50 mcg/kg/day AP-13 i.p.); NS [10 mg/kg DOX i.p.] and NS+AP (NSAP; 10 mg/kg DOX+50 mcg/kg/day AP-13 i.p.). Renal tissues were collected on the 22nd day for light microscopic investigations.

Results: Light microscopic investigations showed that the NS group revealed adhesions between the tuft and Bowman’s capsule, mesangial matrix accumulation in the glomeruli, and tubular damage with dilatation and cast accumulation. In the NSAP group, minimal regression in the glomerular and tubular damage was observed.

Conclusion: The histomorphological changes of AP treatment in a DOX-induced NS model demonstrated a limited therapeutic effect on glomerular and tubular damage in renal tissues.

References

  • Smoyer WE, Mundel P. Regulation of podocyte structure during the devel- opment of nephrotic syndrome. J Mol Med 1998; 76: 172-83. [CrossRef]
  • Krishnan RG, Nephrotic syndrome. Paediatr Child Health 2012; 22: 337- 40. [CrossRef]
  • Ding WY, Saleem MA. Current concepts of the podocyte in nephrotic syn- drome. Kidney Res Clin Pract 2012; 31: 87-93. [CrossRef]
  • Pippin JW, Brinkkoetter PT, Cormack-Aboud FC, Durvasula RV, Hauser PV, Kowalewska J, et al. Inducible rodent models of acquired podocyte dis- eases. Am J Physol Renal Physiol 2009; 296: F213-29. [CrossRef]
  • Ibrahim MA, Ashour OM, Ibrahim YF, El-Bitar HI, Gomaa W, Abdel-Rahim SR. Angiotensin-converting enzyme inhibition and angiotensin AT(1)-re- ceptor antagonism equally improve doxorubicin-induced cardiotoxicity and nephrotoxicity. Pharmacol Res 2009; 60: 373-81. [CrossRef]
  • Ayla S, Seckin I, Tanriverdi G, Cengiz M, Eser M, Soner BC, et al. Doxorubi- cin Induced Nephrotoxicity: Protective Effect of Nicotinamide. Int J Cell Biol 2011; 2011: 1-9. [CrossRef]
  • Soultati A, Mountzios G, Avgerinou C, Papaxoinis G, Pectasides D, Di- mopoulos MA, et al. Endothelial vascular toxicity from chemotherapeu- tic agents: Preclinical evidence and clinical implications. Cancer Treat Rev 2012; 38: 473-83. [CrossRef]
  • Wapstra FH, van Goor H, de Jong PE, Navis G, de Zeeuw D. Dose of doxo- rubicin determines severity of renal damage and responsiveness to ACE-inhibition in experimental nephrosis. J Pharmacol Toxicol Methods 1999; 41: 69-73. [CrossRef]
  • Liu LL, Li QX, Xia L, Li J, Shao L. Differential effects of dihydropyridine calcium antagonists on doxorubicin-induced nephrotoxicity in rats. Tox- icology 2007; 231: 81-90. [CrossRef]
  • Leeuwis JW, Nguyen TQ, Dendooven A, Kok RJ, Goldschmeding R. Targeting podocyte-associated diseases. Adv Drug Deliv Rev 2010; 62: 1325-36. [CrossRef]
  • Cheng H, Harris RC. The glomerulus-a view from the outside-the podo- cyte. Int J Biochem Cell Biol 2010; 42: 1380-7. [CrossRef]
  • Denizli N, Demirci R, Duranay M, Yılmaz B. Glomerüler Endotel Hastalıklarının Tedavisinde Yeni Ufuklar. Turk Neph Dial Transpl 2011; 20: 220-6. [CrossRef]
  • Tatemoto K, Hosoya M, Habata Y, Fujii R, Kakegawa T, Zou MX, et al. Isola- tion and characterization of a novel endogenous peptide ligand for the human APJ receptor. Biochem Biophys Res Commun 1998; 251: 471-6. [CrossRef]
  • O’Dowd BF, Heiber M, Chan A, Heng HH, Tsui LC, Kennedy JL, et al. A human gene that shows identity with the gene encoding the angiotensin receptor is located on chromosome 11. Gene 1993; 136: 355-60. [CrossRef]
  • Sandal S, Tekin S. Adipoz Dokudan Salgınanan Bir Hormon: Apelin. İnönü Sağ Bil Derg 2013; 1: 55-62.
  • Lee DK, Cheng R, Nguyen T, Fan T, Kariyawasam AP, Liu Y, et al. Character- ization of Apelin, the Ligand for the APJ Receptor. J Neurochem 2000; 74: 34-41. [CrossRef]
  • Szokodi I, Tavi P, Földes G, Voutilainen-Myllylä S, Ilves M, Tokola H, et al. Apelin, the Novel Endogenous Ligand of the Orphan Receptor APJ, Reg- ulates Cardiac Contractility. Circ Res 2002; 91: 434-40. [CrossRef]
  • Zhong JC, Huang DY, Liu GF, Jin HY, Yang YM, Lia YF, et al. Effects of all- trans retinoic acid on orphan receptor APJ signaling in spontaneously hypertensive rats. Cardiovasc Res 2005; 65: 743-50. [CrossRef]
  • Hashimoto T, Kihara M, Ishida J, Imai N, Yoshida SI, Toya Y, et al. Apelin Stimulates Myosin Light Chain Phosphorylation in Vascular Smooth Muscle Cells. Arterioscler Thromb Vasc Biol 2006; 26: 1267-72. [CrossRef]
  • Yasuda K, Park HC, Ratliff B, Addabbo F, Hatzopoulos AK, Chander P, et al. Adriamycin nephropathy: a failure of endothelial progenitor cell-in- duced repair. Am J Pathol 2010; 176: 1685-95. [CrossRef]
  • Wang Z, Liu J, Sun W. Effects of asiaticoside on levels of podocyte cy- toskeletal proteins and renal slit diaphragm proteins in adriamycin-in- duced rat nephropathy. Life Sci 2013; 93: 352-8. [CrossRef]
  • Thomas GL, Yang B, Wagner BE, Savill J, El Nahas AM. Cellular apoptosis and proliferation in experimental renal fibrosis. Nephrol Dial Transplant 1998; 13: 2216-26. [CrossRef]
  • Yagmurca M, Erdogan H, Iraz M, Songur A, Ucar M, Fadillioglu E. Caffeic acid phenethyl ester as a protective agent against doxorubicin nephro- toxicity in rats. Clin Chim Acta 2004; 348: 27-34. [CrossRef]
  • Suganami T, Mori K, Tanaka I, Mukoyama M, Sugawara A, Makino H, et al. Role of prostaglandin E receptor EP1 subtype in the development of renal injury in genetically hypertensive rats. Hypertension 2003; 42: 1183-90. [CrossRef]
  • Sakemi T, Ohtsuka N, Tomiyoshi Y, Morito F. Sex difference in progression of adriamycin-induced nephropathy in rats. Am J Nephrol 1996; 16: 540-7. [CrossRef]
  • Bertani T, Poggi A, Pozzoni R, Delaini F, Sacchi G, Thoua Y, et al. Adriamy- cin-induced nephrotic syndrome in rats: sequence of pathologic events. Lab Invest 1982; 46: 16-23.
  • Bo Y, Yuan L. Glomerular Expression of Apelin and its Association with Proteinuria. Indian J Pediatr 2011; 79: 1028-32. [CrossRef]
  • Pedrycz A, Wieczorski M, Czerny K. Pseudoductules in the rat liver in ex- perimental adriamycin-induced nephrotic syndrome. Ann Univ Mariae Curie Sklodowska Med 2002; 57: 154-60.
  • Lee VW, Harrıs DC. Adriamycin nephropathy: A model of focal segmental glomerulosclerosis. Nephrology (Carlton) 2011; 16: 30-8. [CrossRef]
  • Wang Y, Wang YP, Tay YC, Harris DC. Progressive adriamycin nephropathy in mice: sequence of histologic and immunohistochemical events. Kid- ney Int 2000; 58: 1797-804. [CrossRef]
  • O’Carroll AM, Lolait SJ, Harris LE, Pope GR. The apelin receptor APJ: jour- ney from an orphan to a multifaceted regulator of homeostasis. J Endo- crinol 2013; 219: R13-35. [CrossRef]
  • Japp AG, Newby DE. The apelin-APJ system in heart failure Pathophysiologic relevance and therapeutic potential. Biochem Pharmacol 2008; 75: 1882-92. [CrossRef]
  • Soltani Hekmat A, Najafipour H, Nekooian AA, Esmaeli-Mahani S, Javan- mardi K. Cardiovascular responses to apelin in two-kidney-one-clip hy- pertensive rats and its receptor expression in ischemic and non-ischemic kidneys. Regul Pept 2011; 172: 62-8. [CrossRef]
  • Day RT, Cavaglieri RC, Feliers D. Apelin retards the progression of diabetic nephropathy. Am J Physiol Renal Physiol 2013; 304: F788-800. [CrossRef]
  • Zhang BH, Wang W, Wang H, Yin J, Zeng XJ. Promoting effects of the adipo- kine, apelin, on diabetic nephropathy. PLoS One 2013; 8:1-11. [CrossRef]
  • Siddiquee K, Hampton J, Khan S, Zadory D, Gleaves L, Vaughan DE, et al. Apelin protects against angiotensin II-induced cardiovascular fibrosis and decreases plasminogen activator inhibitor type-1 production. J Hy- pertens 2011; 29: 724-31. [CrossRef]
  • Pchejetski D, Foussal C, Alfarano C, Lairez O, Calise D, Guilbeau-Frugier C, et al. Apelin prevents cardiac fibroblast activation and collagen pro- duction through inhibition of sphingosine kinase 1. Eur Heart J 2012; 33: 2360-9. [CrossRef]
  • Wang LY, Diao ZL, Zhang DL, Zheng JF, Zhang QD, Ding JX, et al. The regulatory peptide apelin: a novel inhibitor of renal interstitial fibrosis. Amino Acids 2014; 46: 2693-704. [CrossRef]
  • Principe A, Melgar-Lesmes P, Fernández-Varo G, del Arbol LR, Ros J, Mo- rales-Ruiz M, et al. The hepatic apelin system: a new therapeutic target for liver disease. Hepatology 2008; 48: 1193-201. [CrossRef]

Doksorubisin ile Oluşturulan Nefrotik Sendrom Modelinde Apelinin Böbrek Dokusundaki Histomorfolojik Değişiklikleri

Year 2016, Volume: 6 Issue: 1, 20 - 27, 13.05.2016

Abstract

Amaç: Nefrotik sendrom, böbrek yetmezliğine ilerleyebilen bir hastalıktır. Bir vazoaktif peptid olan apelin, etkisini apelin reseptörüne (APJ) bağlanarak gösterir. Glomerüler arteriollerin endotelyal ve vasküler düz kas hücrelerinde bulunan apelinin, böbrek hemodinamiğini düzenleyerek pre ve post mikrodamarlanma üzerinde etkisinin olduğu görülmüştür. Çalışmamızın amacı, doksorubisin ile oluşturulan nefrotik sendrom modelinde, apelinin glomerüler ve tübüler hasar üzerindeki etkisinin ışık mikroskobu seviyesinde incelenmesidir.

Yöntemler: Çalışmada yetişkin erkek Sprague-Dawley sıçanlar kullanıldı. Sıçanlar rastgele olarak (n=6) Kontrol (K; 1mL/kg i.p. serum fizyolojik (SF)); Apelin+Kontrol (APK; SF ve 50 mcg/kg/gün apelin-13 i.p.); Nefrotik Sendrom (NS; i.p. 10 mg/kg doksorubisin (DOX)) ve Nefrotik Sendrom+Apelin (NSAP; i.p. 10 mg/kg DOX+50 mcg/kg/gün apelin-13) gruplarına ayrıldı. Işık mikroskobu incelemeleri için 22. günde sıçanlar sakrifiye edilerek böbrek dokuları alındı.

Bulgular: Işık mikroskobu incelemelerinde NS grubunda; glomerüllerde mezangial matriks artışı, glomerüler kapiller ve idrar boşluğunda daralma, Bowman kapsülüne yapışma izlendi; tübüllerde ise dilatasyon ve kast oluşumu şeklinde hasar görüldü. NSAP grubunda ise minimal düzeyde hasar gerilemesi gözlendi.

Sonuç: Doksorubisin ile oluşturulan deneysel nefrotik sendrom modelinde apelinin glomerüler ve tübüler hasar üzerinde iyileştirici etkisinin histomorfolojik olarak minimal düzeyde olduğu gösterildi.

References

  • Smoyer WE, Mundel P. Regulation of podocyte structure during the devel- opment of nephrotic syndrome. J Mol Med 1998; 76: 172-83. [CrossRef]
  • Krishnan RG, Nephrotic syndrome. Paediatr Child Health 2012; 22: 337- 40. [CrossRef]
  • Ding WY, Saleem MA. Current concepts of the podocyte in nephrotic syn- drome. Kidney Res Clin Pract 2012; 31: 87-93. [CrossRef]
  • Pippin JW, Brinkkoetter PT, Cormack-Aboud FC, Durvasula RV, Hauser PV, Kowalewska J, et al. Inducible rodent models of acquired podocyte dis- eases. Am J Physol Renal Physiol 2009; 296: F213-29. [CrossRef]
  • Ibrahim MA, Ashour OM, Ibrahim YF, El-Bitar HI, Gomaa W, Abdel-Rahim SR. Angiotensin-converting enzyme inhibition and angiotensin AT(1)-re- ceptor antagonism equally improve doxorubicin-induced cardiotoxicity and nephrotoxicity. Pharmacol Res 2009; 60: 373-81. [CrossRef]
  • Ayla S, Seckin I, Tanriverdi G, Cengiz M, Eser M, Soner BC, et al. Doxorubi- cin Induced Nephrotoxicity: Protective Effect of Nicotinamide. Int J Cell Biol 2011; 2011: 1-9. [CrossRef]
  • Soultati A, Mountzios G, Avgerinou C, Papaxoinis G, Pectasides D, Di- mopoulos MA, et al. Endothelial vascular toxicity from chemotherapeu- tic agents: Preclinical evidence and clinical implications. Cancer Treat Rev 2012; 38: 473-83. [CrossRef]
  • Wapstra FH, van Goor H, de Jong PE, Navis G, de Zeeuw D. Dose of doxo- rubicin determines severity of renal damage and responsiveness to ACE-inhibition in experimental nephrosis. J Pharmacol Toxicol Methods 1999; 41: 69-73. [CrossRef]
  • Liu LL, Li QX, Xia L, Li J, Shao L. Differential effects of dihydropyridine calcium antagonists on doxorubicin-induced nephrotoxicity in rats. Tox- icology 2007; 231: 81-90. [CrossRef]
  • Leeuwis JW, Nguyen TQ, Dendooven A, Kok RJ, Goldschmeding R. Targeting podocyte-associated diseases. Adv Drug Deliv Rev 2010; 62: 1325-36. [CrossRef]
  • Cheng H, Harris RC. The glomerulus-a view from the outside-the podo- cyte. Int J Biochem Cell Biol 2010; 42: 1380-7. [CrossRef]
  • Denizli N, Demirci R, Duranay M, Yılmaz B. Glomerüler Endotel Hastalıklarının Tedavisinde Yeni Ufuklar. Turk Neph Dial Transpl 2011; 20: 220-6. [CrossRef]
  • Tatemoto K, Hosoya M, Habata Y, Fujii R, Kakegawa T, Zou MX, et al. Isola- tion and characterization of a novel endogenous peptide ligand for the human APJ receptor. Biochem Biophys Res Commun 1998; 251: 471-6. [CrossRef]
  • O’Dowd BF, Heiber M, Chan A, Heng HH, Tsui LC, Kennedy JL, et al. A human gene that shows identity with the gene encoding the angiotensin receptor is located on chromosome 11. Gene 1993; 136: 355-60. [CrossRef]
  • Sandal S, Tekin S. Adipoz Dokudan Salgınanan Bir Hormon: Apelin. İnönü Sağ Bil Derg 2013; 1: 55-62.
  • Lee DK, Cheng R, Nguyen T, Fan T, Kariyawasam AP, Liu Y, et al. Character- ization of Apelin, the Ligand for the APJ Receptor. J Neurochem 2000; 74: 34-41. [CrossRef]
  • Szokodi I, Tavi P, Földes G, Voutilainen-Myllylä S, Ilves M, Tokola H, et al. Apelin, the Novel Endogenous Ligand of the Orphan Receptor APJ, Reg- ulates Cardiac Contractility. Circ Res 2002; 91: 434-40. [CrossRef]
  • Zhong JC, Huang DY, Liu GF, Jin HY, Yang YM, Lia YF, et al. Effects of all- trans retinoic acid on orphan receptor APJ signaling in spontaneously hypertensive rats. Cardiovasc Res 2005; 65: 743-50. [CrossRef]
  • Hashimoto T, Kihara M, Ishida J, Imai N, Yoshida SI, Toya Y, et al. Apelin Stimulates Myosin Light Chain Phosphorylation in Vascular Smooth Muscle Cells. Arterioscler Thromb Vasc Biol 2006; 26: 1267-72. [CrossRef]
  • Yasuda K, Park HC, Ratliff B, Addabbo F, Hatzopoulos AK, Chander P, et al. Adriamycin nephropathy: a failure of endothelial progenitor cell-in- duced repair. Am J Pathol 2010; 176: 1685-95. [CrossRef]
  • Wang Z, Liu J, Sun W. Effects of asiaticoside on levels of podocyte cy- toskeletal proteins and renal slit diaphragm proteins in adriamycin-in- duced rat nephropathy. Life Sci 2013; 93: 352-8. [CrossRef]
  • Thomas GL, Yang B, Wagner BE, Savill J, El Nahas AM. Cellular apoptosis and proliferation in experimental renal fibrosis. Nephrol Dial Transplant 1998; 13: 2216-26. [CrossRef]
  • Yagmurca M, Erdogan H, Iraz M, Songur A, Ucar M, Fadillioglu E. Caffeic acid phenethyl ester as a protective agent against doxorubicin nephro- toxicity in rats. Clin Chim Acta 2004; 348: 27-34. [CrossRef]
  • Suganami T, Mori K, Tanaka I, Mukoyama M, Sugawara A, Makino H, et al. Role of prostaglandin E receptor EP1 subtype in the development of renal injury in genetically hypertensive rats. Hypertension 2003; 42: 1183-90. [CrossRef]
  • Sakemi T, Ohtsuka N, Tomiyoshi Y, Morito F. Sex difference in progression of adriamycin-induced nephropathy in rats. Am J Nephrol 1996; 16: 540-7. [CrossRef]
  • Bertani T, Poggi A, Pozzoni R, Delaini F, Sacchi G, Thoua Y, et al. Adriamy- cin-induced nephrotic syndrome in rats: sequence of pathologic events. Lab Invest 1982; 46: 16-23.
  • Bo Y, Yuan L. Glomerular Expression of Apelin and its Association with Proteinuria. Indian J Pediatr 2011; 79: 1028-32. [CrossRef]
  • Pedrycz A, Wieczorski M, Czerny K. Pseudoductules in the rat liver in ex- perimental adriamycin-induced nephrotic syndrome. Ann Univ Mariae Curie Sklodowska Med 2002; 57: 154-60.
  • Lee VW, Harrıs DC. Adriamycin nephropathy: A model of focal segmental glomerulosclerosis. Nephrology (Carlton) 2011; 16: 30-8. [CrossRef]
  • Wang Y, Wang YP, Tay YC, Harris DC. Progressive adriamycin nephropathy in mice: sequence of histologic and immunohistochemical events. Kid- ney Int 2000; 58: 1797-804. [CrossRef]
  • O’Carroll AM, Lolait SJ, Harris LE, Pope GR. The apelin receptor APJ: jour- ney from an orphan to a multifaceted regulator of homeostasis. J Endo- crinol 2013; 219: R13-35. [CrossRef]
  • Japp AG, Newby DE. The apelin-APJ system in heart failure Pathophysiologic relevance and therapeutic potential. Biochem Pharmacol 2008; 75: 1882-92. [CrossRef]
  • Soltani Hekmat A, Najafipour H, Nekooian AA, Esmaeli-Mahani S, Javan- mardi K. Cardiovascular responses to apelin in two-kidney-one-clip hy- pertensive rats and its receptor expression in ischemic and non-ischemic kidneys. Regul Pept 2011; 172: 62-8. [CrossRef]
  • Day RT, Cavaglieri RC, Feliers D. Apelin retards the progression of diabetic nephropathy. Am J Physiol Renal Physiol 2013; 304: F788-800. [CrossRef]
  • Zhang BH, Wang W, Wang H, Yin J, Zeng XJ. Promoting effects of the adipo- kine, apelin, on diabetic nephropathy. PLoS One 2013; 8:1-11. [CrossRef]
  • Siddiquee K, Hampton J, Khan S, Zadory D, Gleaves L, Vaughan DE, et al. Apelin protects against angiotensin II-induced cardiovascular fibrosis and decreases plasminogen activator inhibitor type-1 production. J Hy- pertens 2011; 29: 724-31. [CrossRef]
  • Pchejetski D, Foussal C, Alfarano C, Lairez O, Calise D, Guilbeau-Frugier C, et al. Apelin prevents cardiac fibroblast activation and collagen pro- duction through inhibition of sphingosine kinase 1. Eur Heart J 2012; 33: 2360-9. [CrossRef]
  • Wang LY, Diao ZL, Zhang DL, Zheng JF, Zhang QD, Ding JX, et al. The regulatory peptide apelin: a novel inhibitor of renal interstitial fibrosis. Amino Acids 2014; 46: 2693-704. [CrossRef]
  • Principe A, Melgar-Lesmes P, Fernández-Varo G, del Arbol LR, Ros J, Mo- rales-Ruiz M, et al. The hepatic apelin system: a new therapeutic target for liver disease. Hepatology 2008; 48: 1193-201. [CrossRef]
There are 39 citations in total.

Details

Primary Language Turkish
Journal Section Articles
Authors

Naziye Özkan This is me

Ahmet Özer Şehirli This is me

Mehmet Koç This is me

Şule Çetinel This is me

Publication Date May 13, 2016
Submission Date May 13, 2016
Published in Issue Year 2016 Volume: 6 Issue: 1

Cite

APA Özkan, N., Şehirli, A. Ö., Koç, M., Çetinel, Ş. (2016). Doksorubisin ile Oluşturulan Nefrotik Sendrom Modelinde Apelinin Böbrek Dokusundaki Histomorfolojik Değişiklikleri. Clinical and Experimental Health Sciences, 6(1), 20-27.
AMA Özkan N, Şehirli AÖ, Koç M, Çetinel Ş. Doksorubisin ile Oluşturulan Nefrotik Sendrom Modelinde Apelinin Böbrek Dokusundaki Histomorfolojik Değişiklikleri. Clinical and Experimental Health Sciences. May 2016;6(1):20-27.
Chicago Özkan, Naziye, Ahmet Özer Şehirli, Mehmet Koç, and Şule Çetinel. “Doksorubisin Ile Oluşturulan Nefrotik Sendrom Modelinde Apelinin Böbrek Dokusundaki Histomorfolojik Değişiklikleri”. Clinical and Experimental Health Sciences 6, no. 1 (May 2016): 20-27.
EndNote Özkan N, Şehirli AÖ, Koç M, Çetinel Ş (May 1, 2016) Doksorubisin ile Oluşturulan Nefrotik Sendrom Modelinde Apelinin Böbrek Dokusundaki Histomorfolojik Değişiklikleri. Clinical and Experimental Health Sciences 6 1 20–27.
IEEE N. Özkan, A. Ö. Şehirli, M. Koç, and Ş. Çetinel, “Doksorubisin ile Oluşturulan Nefrotik Sendrom Modelinde Apelinin Böbrek Dokusundaki Histomorfolojik Değişiklikleri”, Clinical and Experimental Health Sciences, vol. 6, no. 1, pp. 20–27, 2016.
ISNAD Özkan, Naziye et al. “Doksorubisin Ile Oluşturulan Nefrotik Sendrom Modelinde Apelinin Böbrek Dokusundaki Histomorfolojik Değişiklikleri”. Clinical and Experimental Health Sciences 6/1 (May 2016), 20-27.
JAMA Özkan N, Şehirli AÖ, Koç M, Çetinel Ş. Doksorubisin ile Oluşturulan Nefrotik Sendrom Modelinde Apelinin Böbrek Dokusundaki Histomorfolojik Değişiklikleri. Clinical and Experimental Health Sciences. 2016;6:20–27.
MLA Özkan, Naziye et al. “Doksorubisin Ile Oluşturulan Nefrotik Sendrom Modelinde Apelinin Böbrek Dokusundaki Histomorfolojik Değişiklikleri”. Clinical and Experimental Health Sciences, vol. 6, no. 1, 2016, pp. 20-27.
Vancouver Özkan N, Şehirli AÖ, Koç M, Çetinel Ş. Doksorubisin ile Oluşturulan Nefrotik Sendrom Modelinde Apelinin Böbrek Dokusundaki Histomorfolojik Değişiklikleri. Clinical and Experimental Health Sciences. 2016;6(1):20-7.

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