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.

Biomarkers of acute kidney injury: the pathway from discovery to clinical adoption

“…Studies in animal models of AKI render data in support of the notion that kidney renin-angiotensin system (RAS) activation contributes to the pathogenesis of AKI [150][151][152][153]. An increase in urine AGT is now considered as one of the most promising biomarkers of AKI progression in patients with acute decompensated heart failure [46,55,154,155].…”

Urinary Angiotensinogen: A Promising Biomarker of AKI Progression in Acute Decompensated Heart Failure: What Does It Mean?

“…The increase in uAGT in AKI is of interest, because it likely reflects local activation of the RAS within the kidney. Studies in animal models of AKI provide evidence in support of the concept that activation of the kidney RAS contributes to the pathogenesis of AKI (13)(14)(15)(16).…”

Angiotensin II, oxidative stress and stem cell therapy: a matter of delicacy

“…As an alternative to what the authors suggest, one might propose that this is an example of the functional switch of the AT 2 receptor, which under pathological conditions supports instead of opposes the AT 1 receptor [7]. Until now, this switch has only been shown for AngII vasoconstrictions [7], and the findings by Kankuri et al [4] might extend this to mitochondrial function. Another complicated observation is that the AT 1 and AT 2 receptor antagonists losartan and PD123319 have an effect in vitro, whereas on the other hand renin is not expressed in BMSCs.…”

“…In the study published in this issue of Clinical Science by Kankuri et al [4], the therapeutic effect of so-called bonemarrow-derived stromal cells (BMSCs) isolated from Sprague-Dawley (SD) rats was compared with that of BMSCs derived from transgenic littermates producing excessive amounts of AngII due Abbreviations: AngII, angiotensin II; AT 1 receptor, angiotensin II type 1 receptor; AT 2 receptor, angiotensin II type 2 receptor; BMSC, bone-marrow-derived stromal cell; RAS, renin-angiotensin system; ROS, reactive oxygen species; SD, Sprague-Dawley; TG, transgenic.…”

“…Another complicated observation is that the AT 1 and AT 2 receptor antagonists losartan and PD123319 have an effect in vitro, whereas on the other hand renin is not expressed in BMSCs. Perhaps mitochondrial function analysis as described by Kankuri et al [4] might be a tool to investigate this hypothetical receptor interaction. Losartan, or its metabolite EXP3174, if formed, would act as an inverse agonist [8].…”