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Exacerbation of acute kidney injury by bone marrow stromal cells from rats with persistent renin-angiotensin system activation

Item Type:Article
Title:Exacerbation of acute kidney injury by bone marrow stromal cells from rats with persistent renin-angiotensin system activation
Creators Name:Kankuri, E. and Mervaala, E.E. and Storvik, M. and Ahola, A.M.J. and Levijoki, J. and Müller, D.N. and Finckenberg, P. and Mervaala, E.M.
Abstract:Hypertension and persistent activation of the renin-angiotensin system (RAS) are predisposing factors for 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 BMSC population vulnerable to alterations even in the early phases of RAS pathology. We isolated TG-BMSCs from young, end organ disease-free rats with increased RAS activation (human angiotensinogen/renin double transgenic rats; dTGR) 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 ischemia-reperfusion-induced AKI. Serum urea and creatinine were measured at 24h and 48h. Acute tubular damage was scored and immunohistochemistry was used for evaluation for markers of inflammation (MCP-1, ED-1), and kidney injury (KIM-1, 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 to 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 shift into a pro-inflammatory phenotype with mitochondrial dysfunction.
Keywords:Acute Kidney Injury, Bone Marrow, Renin-Angiotensin System, Animals, Rats
Source:Clinical Science
Publisher:Portland Press
Page Range:735-747
Date:1 June 2015
Official Publication:https://doi.org/10.1042/CS20140445
PubMed:View item in PubMed

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