Table of Contents Author Guidelines Submit a Manuscript
Stem Cells International
Volume 2017, Article ID 1315378, 15 pages
https://doi.org/10.1155/2017/1315378
Research Article

Mesenchymal Stem Cells Attenuate Cisplatin-Induced Nephrotoxicity in iNOS-Dependent Manner

1Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
2Department of Genetics, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
3Department of Histology and Embryology, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
4Department of Pharmacy, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
5Institute of Anatomy, University of Bern, 3000 Bern 9, Switzerland

Correspondence should be addressed to Vladislav Volarevic; moc.oohay@civeralovrd

Received 9 March 2017; Revised 28 June 2017; Accepted 4 July 2017; Published 30 July 2017

Academic Editor: Silvia Brunelli

Copyright © 2017 Bojana Simovic Markovic et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Mesenchymal stem cells (MSCs) are, due to their immunomodulatory characteristics, utilized in therapy of immune-mediated diseases. We used murine model of cisplatin nephrotoxicity to explore the effects of MSCs on immune cells involved in the pathogenesis of this disease. Intraperitoneal application of MSCs significantly attenuated cisplatin nephrotoxicity, decreased inflammatory cytokines TNF-α and IL-17, and increased anti-inflammatory IL-10, IL-6, nitric oxide (NO), and kynurenine in sera of cisplatin-treated mice. MSC treatment significantly attenuated influx of leukocytes, macrophages, dendritic cells (DCs), neutrophils, CD4+ T helper (Th), and CD8+ cytotoxic T lymphocytes (CTLs) in damaged kidneys and attenuated the capacity of renal-infiltrated DCs, CD4+ Th, and CD8+ CTLs to produce TNF-α and IL-17. Similar effects were observed after intraperitoneal injection of MSC-conditioned medium (MSC-CM) indicating that MSCs exert their beneficial effects in paracrine manner. Inhibition of inducible nitric oxide synthase (iNOS) in MSC-CM resulted with increased number of TNF-α-producing DCs and IL-17-producing CTLs, decreased number of IL-10-producing tolerogenic DCs and regulatory CD4+FoxP3+ T cells, and completely diminished renoprotective effects of MSC-CM. In conclusion, MSCs, in iNOS-dependent manner, attenuated inflammation in cisplatin nephrotoxicity by reducing the influx and capacity of immune cells, particularly DCs and T lymphocytes, to produce inflammatory cytokines.