Abstract

Mezenkimal kök hücrelerin (MKH) bazı böbrek hastalıklarındaki potansiyel koruyucu etkileri bildirilmiştir. Bununla birlikte, fetal böbrek kaynaklı MKH'ların doksorubisin ile indüklenmiş nefropati üzerindeki etkisi henüz araştırılmamıştır. Bu çalışmanın amacı, doksorubisin kaynaklı böbrek hasarı olan ratlara fetal böbrek kaynaklı MKH'ların transplantasyonu yapılarak tedavi edilmesidir. Çalışmada yirmi dört adet Sprague – Dawley ırkı rat üç gruba ayrılmıştır. Bunlar: kontrol grubu, doksorubisin nefropatisi (Sham) grubu ve doksorubisin + MKH ile tedavi edilen gruptur. Çalışmanın başında ve sonunda ratlardan kan alınarak serum biyokimya çalışılmıştır. Böbreklerdeki fonksiyonel değişiklikler sintigrafi ile değerlendirilmiştir. Doksorubisin nefropatisi grubunda mezanjiyal hücre proliferasyonu, tübüler alçı ve glomerüler hipertrofi gibi histopatolojik bulgular gözlenirken, MKH grubunda bu bulgular anlamlı olarak azalmıştır. CD133 ve CD24 pozitif immünreaksiyonlar, en şiddetli ve en sık olarak MKH grubunda gözlenmiştir. Tübüler epitelde pozitif boyanma tespit edilirken glomerulusta immün boyanma gözlenmemiştir. Sonuçlar, Sham grubuna kıyasla MKH grubunda hem fonksiyonel hem de histolojik iyileşmelerin sağlandığını göstermiştir. Sonuç olarak, böbrek hasarı olan hastalara fetal böbrek kaynaklı MKH transplantasyonunun böbrek dokusunun iyileşmesine katkıda bulunduğu düşünülmektedir.

Keywords

• Doksorubisin
• mezenkimal kök hücre
• nefrotoksisite
• rat

Investigation of the effects of fetal rat kidney-derived mesenchymal stem cells implementation on doxorubicin-induced nephropathy in male Sprague–Dawley rats

Abstract

The potential protective effects of mesenchymal stem cells (MSCs) on some kidney diseases have been reported. However, the effect of the fetal kidney–derived (FKD)MSCs on doxorubicin-induced nephropathy has not been studied yet. This study aimed to treat rats with doxorubicin-induced kidney injuries by transplantation of –FKD-MSCs. Twenty-four Sprague-Dawley rats were divided into three groups as control, doxorubicin nephropathy (Sham), and doxorubicin + MSC treated group. Serum biochemistry analysis was performed at the beginning and the end of the study. Functional changes in kidneys were evaluated by scintigraphy. In the doxorubicin nephropathy group, histopathological findings such as mesangial cell proliferation, tubular cast, and glomerular hypertrophy were observed, whereas in the MSC group these findings were significantly reduced. CD133 and CD24 positive immunoreactions were the most severe and frequently observed in the MSC group. While positive staining was detected in the tubular epithelium, there was no immunostaining observed in the glomerulus. The results showed that both functional and histological improvements were achieved in the MSC group compared to the Sham group. In conclusion, transplantation of fetal kidney - derived MSCs into patients with renal damage is thought to contribute to the healing of the renal tissue.

Keywords

• doxorubicin
• mesenchymal stem cell
• Nephrotoxicity
• rat

References

1. Alfarano C, Roubeix C, Chaaya R, et al (2012): Intraparenchymal injection of bone marrow mesenchymal stem cells reduces kidney fibrosis after ischemia - reperfusion in cyclosporine immunosuppressed rats. Cell Transplant, 21, 2009-2019.
2. Anan HH, Zidan RA, Shaheen MA, et al (2016): Therapeutic efficacy of bone marrow derived mesenchymal stromal cells versus losartan on adriamycin-induced renal cortical injury in adult albino rats. Cytotherapy, 18, 970-984.
3. El-Ansary M, Saadi G, AbdEl - Hamid SM (2012): Mesenchymal stem cells are a rescue approach for recovery of deteriorating kidney function. Nephrology, 17, 650-657.
4. Gardner HL, London CA, Portela RA, et al (2015): Maintenance therapy with toceranib following doxorubicin-based chemotherapy for canine splenic hemangiosarcoma. BMC Vet Res, 11, 131.
5. Gultekin SS, Odabas O, Ginis Z¸ et al (2013): Scintigraphic comparison of renal ischemia–reperfusion injury models in rats: Correlations with Biochemical and Histopathological Findings. Ann Nucl Med, 27, 564-571.
6. Guo J, Zou Y, Wu Z, et al (2014): Protective effects of mesenchymal stromal cells on Adriamycin - induced minimal change nephrotic syndrome in rats and possible mechanisms. Cytotherapy, 16, 471-484.
7. Herrera MB, Bussolati B, Bruno S, et al (2007): Exogenous mesenchymal stem cells localize to the kidney by means of CD44 following acute tubular injury. Kidney Int, 72, 430-441.
8. Huang Z, He L, Huang D, et al (2015): Icariin protects rats against 5 / 6 nephrectomy - induced chronic kidney failure by increasing the number of renal stem cells. BMC Complement Altern Med, 15, 378.

9. Kubat GB, Ozler M, Ulger O, et al (2020): The effects of mesenchymal stem cell mitochondrial transplantation on doxorubicin‐mediated nephrotoxicity in rats. J Biochem Mol Toxicol, e22612.
10. Lee VW, Harris DC (2011): Adriamycin nephropathy: A model of focal segmental glomerulosclerosis. Nephrology, 16, 30-38.
11. Ma H, Wu Y, Zhang W, et al (2013): The effect of mesenchymal stromal cells on doxorubicin-induced nephropathy in rats. Cytotherapy, 15, 703-711.
12. Matsuyama A, Poirier VJ, Mantovani F, et al (2017): Adjuvant Doxorubicin with or without Metronomic Cyclophosphamide for Canine Splenic Hemangiosarcoma. J Am Anim Hosp Assoc, 53, 304-312.
13. Morigi M, Benigni A (2013): Mesenchymal stem cells and kidney repair. Nephrol Dial Transplant, 28, 788-793.
14. Morigi M, Imberti B, Zoja C, et al (2004): Mesenchymal stem cells are renotropic, helping to repair the kidney and improve function in acute renal failure. J Am Soc Nephrol, 15, 1794-1804.
15. Morigi M, Rota C, Remuzzi G (2016): Mesenchymal Stem Cells in Kidney Repair. Methods Mol Biol, 1416, 89-107.
16. Ogilvie GK, Fettman MJ, Mallinckrodt CH, et al (2000): Effect of fish oil, arginine, and doxorubicin chemotherapy on remission and survival time for dogs with lymphoma: A double-blind, randomized placebo-controlled study. Cancer, 88, 1916-1928.
17. Papazova DA, Oosterhuis NR, Gremmels H, et al (2015): Cell-based therapies for experimental chronic kidney disease: a systematic review and meta-analysis. Disease Models & Mechanisms, 8, 281-293.
18. Patel DM, Shah J, Srivastava AS (2013): Therapeutic Potential of Mesenchymal Stem Cells in Regenerative Medicine. Stem Cells Int, 2013, 1-15.
19. Quimby JM, Webb TL, Randall E, et al (2016): Assessment of intravenous adipose-derived allogeneic mesenchymal stem cells for the treatment of feline chronic kidney disease: A randomized, placebo-controlled clinical trial in eight cats. J Feline Med Surg, 18, 165-171.
20. Rühle A, Lopez Perez R, Zou B, et al (2019): The Therapeutic Potential of Mesenchymal Stromal Cells in the Treatment of Chemotherapy-Induced Tissue Damage. Stem Cell Reviews, 15, 356-373.
21. Selim RE, Ahmed HH, Abd-Allah SH, et al (2019): Mesenchymal Stem Cells: a Promising Therapeutic Tool for Acute Kidney Injury. Appl Biochem Biotechnol, 189, 284-304.
22. Villanueva S, Carreno JE, Salazar L, et al (2013): Human mesenchymal stem cells derived from adipose tissue reduce functional and tissue damage in a rat model of chronic renal failure. Clin Sci, 125, 199-210.
23. Wise F, Ricardo SD (2012): Mesenchymal stem cells in kidney inflammation and repair. Nephrology, 17, 58-71.
24. Zhang Y, Xu Y, Qi Y, et al (2017): Protective effects of dioscin against doxorubicin-induced nephrotoxicity via adjusting FXR-mediated oxidative stress and inflammation. Toxicology, 378, 53-64.
25. Zoja C, Garcia PB, Rota C, et al (2012): Mesenchymal stem cell therapy promotes renal repair by limiting glomerular podocyte and progenitor cell dysfunction in Adriamycin - induced nephropathy. Am J Physiol, 303, 1370-1381.