Introduction: Acute tubular necrosis (ATN) is the most prevalent cause of acute renal failure (ARF).Mesenchymal stem cell transplantation has been studied as a potential treatment for renal dysfunction due to ATN. Inducible nitric oxide synthase (iNOS), bone morphogenetic protein-7 (BMP-7) and B-cell lymphoma 2 (Bcl-2) are surrogate markers of renal tubular epithelial regeneration and subsequent recovery of renal function following ATN. Methods: Serum creatinine (Scr) and blood urea nitrogen (BUN), as well as expression of iNOS, BMP-7 and Bcl-2 in gentamycin-induced ATN rat kidneys was investigated after human umbilical cord-derived mesenchymal stem cell (HUC-MSC) transplantation. Immunohistochemical staining was performed in 3 groups of rats: gentamycin-induced ATN treated with HUC-MSC, gentamycin-induced ATN without HUC-MSC, and untreated rats not receiving any treatments. Results: HUC-MSC transplantation led to a reduction in Scr and BUN in the kidneys of rats with gentamycin-induced ATN. Expression of iNOS in the HUC-MSC treated group occurred later and the expression levels were much lower during gentamycin-induced ATN compared to rats with ATN that were not treated with HUC-MSC. The expression of BMP-7 and Bcl-2 in the MSC-transplanted group was significantly increased compared to both control groups of rats with injured and healthy renal tubules. Conclusions: HUC-MSCs induce renal protection in a rat model of gentamycin-induced ATN, which is associated with reduced iNOS expression and up-regulation of Bcl-2 and BMP-7.
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Li, F. , Xiong, F. , Zhang, Y. , Li, Y. , Zhao, H. , Cho, S. , Ichim, T. , Yang, X. and Hu, X. (2013) Therapeutic effects of human umbilical cord-derived mesenchymal stem cells against acute tubular necrosis quantified through measures of iNOS, BMP-7 and Bcl-2. Open Journal of Regenerative Medicine, 2, 31-38. doi: 10.4236/ojrm.2013.22006.
 Pruchnicki, M.C. and Dasta, J.F. (2002) Acute renal failure in hospitalized patients. The Annals of Pharmacotherapy, 36, 1261-1267. doi:10.1345/aph.1A339
 Kelly, K.J. and Molitoris, B.A. (2000) Acute renal failure in the new millennium: Time to consider combination therapy. Seminars in Nephrology, 20, 4-19．
 Chhabra, P. and Brayman, K.L. (2009) The use of stem cells in kidney disease. Current Opinion in Organ Transplantation, 14, 72-78.
 Benjamin, D.H. and Joseph, V.B. (2008) Mesenchymal stem cells in acute kidney injury. Annual Review of Medicine, 59, 311-325.
 Hiroshi, A., Daniel, R.M. and Kirstan, K.M. (2010) Therapeutic application of mesenchymal stem cells to repair kidney injury. Journal of Urology, 184, 26-33.
 Morigi, M., Imberti, B., Zoja, C., Corna, D., Tomasoni, S., Abbate, M., Rottoli, D., Angioletti, S., Benigni, A., Perico, N., Alison, M. and Remuzzi, G. (2004) Mesenchymal stem cells are renotropic, helping to repair the kidney and improve function in acute renal failure. Journal of the American Society of Nephrology, 15, 1794-1804.
 Herrera, M.B., Bussolati, B., Bruno, S., Fonsato, V., Romanazzi, G.M. and Camussi, G. (2004) Mesenchymal stem cells contribute to the renal repair of acute tubular epithelial injury. International Journal of Molecular Medicine, 14, 1035-1041.
 Imberti, B., Morigi, M., Tomasoni, S., Rota, C., Corna, D., Longaretti, L., Rottoli, D., Valsecchi, F., Benigni, A., Wang, J., Abbate, M., Zoja, C. and Remuzzi, G. (2007) Insulin-like growth factor-1 sustains stem cell mediated renal repair. Journal of the American Society of Nephrology, 18, 2921-2928. doi:10.1681/ASN.2006121318
 Fujigaki, Y., Sakakima, M., Sun, Y., Goto, T., Ohashi, N., Fukasawa, H., Tsuji, T., Yamamoto, T. and Hishida, A. (2007) Immunohistochemical study on caveolin-1alpha in regenerating process of tubular cells in gentamicin-induced acute tubular injury in rats. Virchows Archiv, 450, 671-681. doi:10.1007/s00428-007-0417-4
 Goto, T., Fujigaki, Y., Sun, D.F., Yamamoto, T. and Hishida, A. (2004) Plasma protein extravasation and vascular endothelial growth factor expression with endothelial nitric oxide synthase induction in gentamicin-induced acute renal failure in rats. Virchows Archiv, 444, 362-374.
 Qian, J.Q. (2004) Internal medicine. 6th Edition, The People’s Medical Publishing House, Beijing.
 Sun, L.Y., Wang, D.D., Liang, J., Zhang, H.Y., Feng, X.B., Wang, H., Hua, B.Z., Liu, B.J., Ye, S.Q., Hu, X., Xu, W.R., Zeng, X.F., Hou, Y.Y., Gilkeson, G.S., Silver, R.M., Lu, L.W. and Shi, S.T. (2010) Umbilical cord mesenchymal stem cell transplantation in severe and refractory systemic lupus erythematosus. Arthritis & Rheumatism, 62, 2467-2475. doi:10.1002/art.27548
 da Silva Meirelles, L., Chagastelles, P.C. and Nardi, N.B. (2006) Mesenchymal stem cells reside in virtually all post-natal organs and tissues. Journal of Cell Science, 119, 2204-2213. doi:10.1242/jcs.02932
 Tsai, P.C., Fu, T.W., Chen, Y.M., Ko, T.L., Chen, T.H., Shih, Y.H., Hung, S.C. and Fu, Y.S. (2009) The therapeutic potential of human umbilical mesenchymal stem cells from Wharton’s jelly in the treatment of rat liver fibrosis. Liver Transplantation, 15, 484-495. doi:10.1002/lt.21715
 Caplan, A.L. (1991) Mesenchymal stem cells. Journal of Orthopaedic Research, 9, 641-650.
 Kale, S., Karihaloo, A., Clark, P.R., Kashgarian, M., Krause, D.S. and Cantley, L.G. (2003) Bone marrow stem cells contribute to repair of the ischemically injured renal tubule. Journal of Clinical Investigation, 112, 42-49.
 Buck, K.S., Foster, E.M., Watson, D., Barratt, J., Pawluczyk, I.Z., Knight, J.F., Feehally, J. and Allen, A.C. (2002) Expression of T cell receptor variable families by bone marrow gamma delta T cells in patients with IgA nephropathy. Clinical & Experimental Immunology, 127, 527-532. doi:10.1111/j.1365-2249.2002.01784.x
 Liu, G.F., Qu, S.L., Yao, P., He, L., Zheng, R.F., Cai, Y.R., Li, S.H. and Zhao, Y.N. (2006) The relations between iNOS and ischemic ARF, as well as the effect of extrinsic L-arginine on ARF. Sichuan Medical Journal, 27, 13-15.
 Goligorsky, M.S., Brodsky, S.V. and Noiri, E. (2002) Nitric oxide in acute renal failure: NOS versus NOS. Kidney International, 61, 855-861.
 Martin, M.U. and Wesche, H. (2002) Summary and comparison of the signaling mechanisms of the Toll/interleuk in-1 receptor family. Biochimica et Biophysica Acta, 1592, 265-280. doi:10.1016/S0167-4889(02)00320-8
 Sauter, B., Albert, M.L., Francisco, L., Larsson, M., Somersan, S. and Bhardwaj, N. (2000) Consequences of cell death: Exposure to necrotic tumor cells, but not primary tissue cells or apoptotic cells, induces the maturation of immunostimulatory dendritic cells. The Journal of Experimental Medicine, 191, 423-434.
 Huang, J.E., Li, X.K., Yang, Z.P. and Liangk, Z.D. (2002) Changes of cellular ultrastructure on protective and therapeutic effect of bFGF acting against gentamicin nephrotoxicity. Anatomy Research, 24, 110-112.
 Ozkaynak, E., Rueger, D.C., Drier, E.A., Corbett, C., Ridge, R.J., Sampath, T.K. and Oppermann, H. (1990) OP-1 cDNA encodes an osteogenic protein in the TGF-beta family. EMBO Journal, 9, 2085-2093.
 Gould, S.E., Day, M., Jones, S.S. and Dorai, H. (2002) BMP-7 regulates chemokine, cytokine, and hemodynamic gene expression in proximal tubule cells. Kidney International, 61, 51-60. doi:10.1046/j.1523-1755.2002.00103.x
 Zeisberg, M., Hanai, J., Sugimoto, H., Mammoto, T., Charytan, D., Strutz, F. and Kalluri, R. (2003) BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nature Medicine, 7, 964-968. doi:10.1038/nm888
 Lee, H.T., Xu, H., Siegel, C.D. and Krichevsky, I.E. (2003) Local anesthetics induce human renal cell apoptosis. American Journal of Nephrology, 23, 129-139.
 Hauser, P. and Oberbauer, R. (2002) Tubular apoptosis in the pathophysiology of renal disease. Wiener Klinische Wochenschrift, 114, 671-677.
 Zhou, H., Kato, A., Yasuda, H., Odamaki, M., Itoh, H. and Hishida, A. (2003) The induction of heat shock protein-72 attenuates cisplatin-induced acute renal failure in rats. Pflügers Archiv, 446, 116-124.
 Huang, L.H., Zhang, G.Q., Ye, R.G., Li, Y.J., Chen, X.H. and Guan, W.M. (2000) The role of cell proliferation and apoptosis in renal tubulointerstitial fibrosis caused by unilateral ureteral obstruction. Chinese Journal of Nephrology, 16, 24-27.
 Hale, A.J., Smith, C.A., Sutherland, L.C., Stoneman, V.E., Longthorne, V.L., Culhane, A.C. and Williams, G.T. (1996) Apoptosis: Molecular regulation of cell death. European Journal of Biochemistry, 236, 1-26.
 Korsmeyer, S.J. (1999) Bcl-2 gene family and the regulation of programmed cell death. Cancer Research, 59, 1693-1700.
 Tsujimoto, Y., Shimizu, S., Eguchi, Y., Kamiike, W. and Matsuda, H. (1997) Bcl-2 and Bcl-XL block apoptosis as well as necrosis possible involvement of common mediators in apoptosic and necrotic signal transduction pathways. Leukemia, 11, 380-382.
 Takahashi, M., Saito, H., Okuyama, T., Miyashita, T., Kosuga, M., Sumisa, F., Yamada, M., Ebinuma, H. and Ishii, H. (1999) Overexpression of Bcl-2 protects human hepatoma cells from Fas-antibody-mediated apoptosis. Journal of Hepatology, 31, 315-322.