title: Exacerbation of acute kidney injury by bone marrow stromal cells from rats with persistent renin-angiotensin system activation.
abstract: 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.
authors.affiliation: *Faculty of Medicine, Department of Pharmacology, University of Helsinki, Finland.
authors.forename: Esko
authors.initials: E
authors.lastname: Kankuri
authors.affiliation: *Faculty of Medicine, Department of Pharmacology, University of Helsinki, Finland.
authors.forename: Elina E
authors.initials: EE
authors.lastname: Mervaala
authors.affiliation: †School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
authors.forename: Markus
authors.initials: M
authors.lastname: Storvik
authors.affiliation: *Faculty of Medicine, Department of Pharmacology, University of Helsinki, Finland.
authors.forename: Aija M J
authors.initials: AM
authors.lastname: Ahola
authors.affiliation: ‡Orion Pharma Research Center, Espoo, Finland.
authors.forename: Jouko
authors.initials: J
authors.lastname: Levijoki
authors.affiliation: §Max Delbrück Center, Experimental and Clinical Research Center, Berlin, Germany.
authors.forename: Dominik N
authors.initials: DN
authors.lastname: Müller
authors.affiliation: *Faculty of Medicine, Department of Pharmacology, University of Helsinki, Finland.
authors.forename: Piet
authors.initials: P
authors.lastname: Finckenberg
authors.affiliation: *Faculty of Medicine, Department of Pharmacology, University of Helsinki, Finland.
authors.forename: Eero M
authors.initials: EM
authors.lastname: Mervaala
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology / Q000235:genetics / Q000503:physiopathology*; D000209:Acute-Phase Proteins / Q000235:genetics / Q000378:metabolism; D000808:Angiotensinogen / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D006973:Hypertension / Q000235:genetics / Q000503:physiopathology; D007150:Immunohistochemistry; D000071068:Lipocalin-2; D054834:Lipocalins / Q000235:genetics / Q000378:metabolism; D045164:Mesenchymal Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010101:Oxygen Consumption; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D017382:Reactive Oxygen Species / Q000378:metabolism; D051437:Renal Insufficiency / Q000235:genetics / Q000503:physiopathology; D012083:Renin / Q000235:genetics / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000235:genetics / Q000502:physiology*
chemical_list: D000209:Acute-Phase Proteins; D000808:Angiotensinogen; D015815:Cell Adhesion Molecules; D018932:Chemokine CCL2; D000071068:Lipocalin-2; D054834:Lipocalins; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; D012083:Renin; C491766:Ccl2 protein, rat; C110936:Havcr1 protein, rat; C097278:Lcn2 protein, rat