Hypertension and persistent activation of the renin–angiotensin system (RAS) are predisposing factors for the development of acute kidney injury (AKI). Although bone-marrow-derived stromal cells (BMSCs) have shown therapeutic promise in treatment of AKI, the impact of pathological RAS on BMSC functionality has remained unresolved. RAS and its local components in the bone marrow are involved in several key steps of cell maturation processes. This may also render the BMSC population vulnerable to alterations even in the early phases of RAS pathology. We isolated transgenic BMSCs (TG-BMSCs) from young end-organ-disease-free rats with increased RAS activation [human angiotensinogen/renin double transgenic rats (dTGRs)] that eventually develop hypertension and die of end-organ damage and kidney failure at 8 weeks of age. Control cells (SD-BMSCs) were isolated from wild-type Sprague–Dawley rats. Cell phenotype, mitochondrial reactive oxygen species (ROS) production and respiration were assessed, and gene expression profiling was carried out using microarrays. Cells’ therapeutic efficacy was evaluated in a rat model of acute ischaemia/reperfusion-induced AKI. Serum urea and creatinine were measured at 24 h and 48 h. Acute tubular damage was scored and immunohistochemistry was used for evaluation for markers of inflammation [monocyte chemoattractant protein (MCP-1), ED-1], and kidney injury [kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL)]. TG-BMSCs showed distinct mitochondrial morphology, decreased cell respiration and increased production of ROS. Gene expression profiling revealed a pronounced pro-inflammatory phenotype. In contrast with the therapeutic effect of SD-BMSCs, administration of TG-BMSCs in the AKI model resulted in exacerbation of kidney injury and high mortality. Our results demonstrate that early persistent RAS activation can dramatically compromise therapeutic potential of BMSCs by causing a shift into a pro-inflammatory phenotype with mitochondrial dysfunction.
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Research Article|
March 17 2015
Exacerbation of acute kidney injury by bone marrow stromal cells from rats with persistent renin–angiotensin system activation
Esko Kankuri;
Esko Kankuri
*Faculty of Medicine, Department of Pharmacology, University of Helsinki, Finland
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Elina E. Mervaala;
Elina E. Mervaala
*Faculty of Medicine, Department of Pharmacology, University of Helsinki, Finland
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Markus Storvik;
Markus Storvik
†School of Pharmacy, University of Eastern Finland, Kuopio, Finland
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Aija M.J. Ahola;
Aija M.J. Ahola
*Faculty of Medicine, Department of Pharmacology, University of Helsinki, Finland
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Jouko Levijoki;
Jouko Levijoki
‡Orion Pharma Research Center, Espoo, Finland
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Dominik N. Müller;
Dominik N. Müller
§Max Delbrück Center, Experimental and Clinical Research Center, Berlin, Germany
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Piet Finckenberg;
Piet Finckenberg
*Faculty of Medicine, Department of Pharmacology, University of Helsinki, Finland
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Eero M. Mervaala
*Faculty of Medicine, Department of Pharmacology, University of Helsinki, Finland
Correspondence: Professor Eero Mervaala (email [email protected]).
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Publisher: Portland Press Ltd
Received:
July 22 2014
Revision Received:
December 15 2014
Accepted:
December 23 2014
Accepted Manuscript online:
December 23 2014
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2015 Biochemical Society
2015
Clin Sci (Lond) (2015) 128 (11): 735–747.
Article history
Received:
July 22 2014
Revision Received:
December 15 2014
Accepted:
December 23 2014
Accepted Manuscript online:
December 23 2014
Connected Content
A commentary has been published:
Angiotensin II, oxidative stress and stem cell therapy: a matter of delicacy
Citation
Esko Kankuri, Elina E. Mervaala, Markus Storvik, Aija M.J. Ahola, Jouko Levijoki, Dominik N. Müller, Piet Finckenberg, Eero M. Mervaala; Exacerbation of acute kidney injury by bone marrow stromal cells from rats with persistent renin–angiotensin system activation. Clin Sci (Lond) 1 June 2015; 128 (11): 735–747. doi: https://doi.org/10.1042/CS20140445
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