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See detailAdministration of mesenchymal stromal cells before renal ischemia/reperfusion attenuates kidney injury and modulates renal lipid metabolism in rats
ERPICUM, Pauline ULiege; Rowart, Pascal ULiege; POMA, Laurence ULiege et al

in Transplant International (2017, September), 30(S2), 9004

Background: Mesenchymal stromal cells (MSC) have been demonstrated to attenuate renal ischemia/reperfusion (I/R) damage in rodents. The mecha- nisms of such nephroprotection remain unclear. Materials and ... [more ▼]

Background: Mesenchymal stromal cells (MSC) have been demonstrated to attenuate renal ischemia/reperfusion (I/R) damage in rodents. The mecha- nisms of such nephroprotection remain unclear. Materials and Methods: Male Lewis rats aged of 8–10 weeks received tail i.v injection of 1.5x106 MSC in 1 mL saline (MSCD-7, n = 11) or saline alone (SD- 7, n = 6) 7 days before renal I/R. Left renal ischemia (by clamping the renal pedicle) lasted 45 min. Right nephrectomy was simultaneously performed. Blood sample was collected from inferior vena cava 48 h post reperfusion. Renal function was assessed by measuring serum creatinine (SCr) levels. Expressions of inflammatory and apoptotic markers by real-time (RT)-qPCR were comparatively quantified. High-throughput RNA sequencing was applied to MSCD-7 vs. SD-7 non-ischemic right kidneys. Relevant pathways were detected using an Over-Representation Analysis with WebGestalt, and confirmed by RT-qPCR. Results: Scr levels reached 1.4 ` 0.7 vs. 2.4 ` 0.8 mg/dL in MSCD-7 vs. SD-7 group (p < 0.05). MSC infusion significantly reduced mRNA expression of Casp3, Hsp 70, Kim-1, Mcp-1 and Il-6 and increased mRNA expression of Bcl compared to saline. Among 25 908 genes, 748 were identified as significantly differentially expressed (False Discovery Rate (FDR), <0.05) between MSCD-7 and SD-7 non-ischemic kidneys. Among the most affected metabolic pathways, renal lipid metabolism was significantly altered, with down-regulation of fatty acid biosynthesis and an up-regulation of PPARa pathway in MSCD-7 vs. SD-7 groups. By immunoblotting, PPARa and phosphorylated-PPARa were significantly increased in MSCD-7 vs. SD-7 kidneys, in both non-ischemic and ischemic conditions. Moreover, levels of malondialdehyde-derived lipid peroxidation products were decreased in MSCD-7 ischemic kidneys in comparison to SD-7 ischemic kidneys. Conclusion: MSC infusion at day 7 prior injury critically impacts renal lipid metabolism, which may condition kidney parenchyma against I/R. [less ▲]

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See detailAdministration of mesenchymal stromal cells before renal ischemia/reperfusion attenuates kidney injury and may modulate renal lipid metabolism in rats.
ERPICUM, Pauline ULiege; Rowart, Pascal ULiege; POMA, Laurence ULiege et al

in Scientific Reports (2017), 7(1), 8687

Mesenchymal stromal cells (MSC) have been demonstrated to attenuate renal ischemia/reperfusion (I/R) damage in rodent models. The mechanisms of such nephro-protection remain largely unknown. Furthermore ... [more ▼]

Mesenchymal stromal cells (MSC) have been demonstrated to attenuate renal ischemia/reperfusion (I/R) damage in rodent models. The mechanisms of such nephro-protection remain largely unknown. Furthermore, the optimal timing of MSC administration has been poorly investigated. Here, we compare the impact of MSC injection 7 days before (MSCD - 7) versus 1 day after (MSCD + 1) renal I/R in rats. Control groups received equivalent volumes of saline at similar time-points (SD - 7 and SD + 1). Right nephrectomy was performed, and left renal ischemia lasted 45 min. After 48-hour reperfusion, we observed significantly improved renal function parameters, reduced apoptotic index and neutrophil/macrophage infiltration in kidney parenchyma, and lower expression of tubular damage markers and pro-inflammatory cytokines in MSCD - 7 in comparison to MSCD + 1 and saline control groups. Next, comparative high-throughput RNA sequencing of MSCD - 7 vs. SD - 7 non-ischemic right kidneys highlighted significant down-regulation of fatty acid biosynthesis and up-regulation of PPAR-alpha pathway. Such a preferential regulation towards lipid catabolism was associated with decreased levels of lipid peroxidation products, i.e. malondialdehyde and 4-hydroxy-2-nonenal, in MSCD - 7 versus SD - 7 ischemic kidneys. Our findings suggest that MSC pretreatment may exert protective effects against renal I/R by modulating lipid metabolism in rats. [less ▲]

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See detailDiscovery and pharmacological characterization of succinate receptor (SUCNR1/GPR91) agonists
Geubelle, Pierre ULiege; Gilissen, Julie; Dilly, Sebastien et al

in British Journal of Pharmacology (2017), 174(9), 796-808

Background and Purpose The succinate receptor (SUCNR1 or GPR91) has been described as a metabolic sensor that may be involved in homeostasis. Notwithstanding its implication in important (patho ... [more ▼]

Background and Purpose The succinate receptor (SUCNR1 or GPR91) has been described as a metabolic sensor that may be involved in homeostasis. Notwithstanding its implication in important (patho)physiological processes, the function of SUCNR1 has remained elusive because no pharmacological tools were available. We report on the discovery of the first family of synthetic potent agonists. Experimental Approach We screened a library of succinate analogues and analysed their activity on SUCNR1. In addition, we modelled a pharmacophore and a binding site for the receptor. New agonists were identified based on the information provided by these two approaches. Their activity was studied in various bioassays, including measurement of cAMP levels, [Ca2+]i mobilisation, TGF-α shedding and recruitment of arrestin 3. The in vivo impact of SUCNR1 activation by these new agonists was evaluated on rat blood pressure. Key Results We identified cis-epoxysuccinic acid and cis-1,2-cyclopropanedicarboxylic acid as agonists with an efficacy similar to the one of succinic acid. Interestingly, cis-epoxysuccinic acid was characterized by a 10 to 20 fold higher potency than succinate on the receptor. For example, cis-epoxysuccinic acid reduced cAMP levels with a pEC50 = 5.57 ± 0.02 (EC50 = 2.7 μM) as compared to succinate pEC50 = 4.54 ± 0.08 (EC50 = 29 μM). The rank order of potency of the three agonists was the same in all bioassays tested. In vivo, cis-epoxysuccinic and cis-1,2-cyclopropanedicarboxylic acid increased rat blood pressure to the same extent as succinate did. Conclusions and Implications We provide new agonist tools for SUCNR1 that should facilitate further research on this understudied receptor. [less ▲]

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See detailintravenous administration of mesenchymal stream cells modulates renal lipid metabolism in rats
ERPICUM, Pauline ULiege; Rowart, Pascal ULiege; POMA, Laurence ULiege et al

Conference (2017, March 16)

Mesenchymal stromal cells (MSC) have been shown to attenuate renal ischemia/reperfusion (I/R) injury in rodents. Still, the mechanisms of such a nephroprotection remain unclear. Here, rats were ... [more ▼]

Mesenchymal stromal cells (MSC) have been shown to attenuate renal ischemia/reperfusion (I/R) injury in rodents. Still, the mechanisms of such a nephroprotection remain unclear. Here, rats were intravenously infused with MSC (1.5x10^6 cells in 1 ml saline; MSCD-7 group, n=6) or equivalent volume of saline (SD-7 group, n=6) 7 days before kidney sampling. High-throughput RNA sequencing technology was used to compare transcriptomic renal profiles, using TopHat and Cufflinks open-source software tools. A total of 494 and 256 genes were found to be significantly (q-value <.05) down- and up-regulated in mscd-7 versus sd-7 groups, respectively. Hierarchical cluster analysis by “david” “webgestalt” softwares highlighted that the metabolic pathways mostly affected msc included adipogenesis, insulin signalling, fatty acid (fa) biosynthesis, il-6 b-cell receptor il-3 pathway nuclear receptors involved lipid me- tabolism. Real-time qpcr immunoblotting analyses confirmed pivotal enzymes of fa biosynthesis were significantly downregulated group, whereas expression ppar alpha, a transcription factor oxidation, was induced msc. Additional- ly, fat />CD36 – a key regulator of membrane uptake of FA – was increased in MSCD-7 kidneys, with a preferential localization in proximal tubules (PT). As a whole, our data suggest that MSC infusion causes critical modifications of lipid metabolism, including (i) down-regulation of FA biosynthesis; (ii) activation of PPAR alpha pathway, and (iii) prioritization of FA as sources of energy in PT cells, which may eventually prevent lipid peroxidation and attenuate renal I/R damage. [less ▲]

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See detailImpact of timing administration of mesenchymal stromal cells on serum creatinine following renal ischemia/ reperfusion in rats
ERPICUM, Pauline ULiege; Rowart, Pascal ULiege; POMA, Laurence ULiege et al

in Transplant International (2015, November), 28(S4), 1129

Experimental models of renal ischemia/reperfusion (I/R) have suggested protective effects of mesenchymal stromal cells (MSC) therapy. Still, param- eters of MSC injection, including volume, route and ... [more ▼]

Experimental models of renal ischemia/reperfusion (I/R) have suggested protective effects of mesenchymal stromal cells (MSC) therapy. Still, param- eters of MSC injection, including volume, route and timing of cell administration, remain largely debated. Particularly, MSC infusion in mouse has been shown to be beneficial “a priori” but deleterious “a posteriori” of renal I/R injury. In order to further investigate the influence of the timing of MSC administration, we used 10-week-old Lewis rats categorized in 4 groups. Groups 1 (MSC D-7, n = 10) and 2 (MSC D + 1, n = 7) received caudal i.v. injection of MSC (1.5 9 106 in 1 ml of saline) 7 days before or 1 day after renal I/R, respectively. Control groups 3 (saline D-7, n = 6) and 4 (saline D + 1, n = 6) received equal volume of saline at similar time points. Left renal ischemia (by clamping of the renal pedicle) lasted 45 min. Right nephrectomy was simultaneously performed. Blood sample was collected from inferior vena cava at 48 h post reperfusion. MSC phenotype was confirmed by FACS analysis. In groups 1 and 3, serum creatinine (SCr) reached 1.4 ` 0.7 versus 2.4 ` 0.8 mg/dl, respectively (p < 0.05). In groups 2 and 4, SCr was 4.9 ` 0.7 versus 3.3 ` 0.9 mg/dl, respectively (p < 0.001). Furthermore, SCr levels were statistically worse when MSC were administered after renal I/R in comparison to a priori infusion (p < 0.0001). In conclusion, MSC administration 7 days prior to renal I/R attenuates kidney injury in comparison to (i) saline infusion or (ii) MSC infusion 1 day after renal I/R. Conversely, on the basis of SCr levels, MSC therapy performed after renal I/R worsens kidney injury in rats. [less ▲]

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See detailActivation of the calcium-sensing receptor before renal ischemia/reperfusion exacerbates kidney injury
WEEKERS, Laurent ULiege; De Tullio, Pascal ULiege; BOVY, Christophe ULiege et al

in American Journal of Translational Research (2015), 7(1), 128-138

Activation of the calcium-sensing receptor (CaSR) by ischemia/reperfusion (I/R) favours apoptosis in cardiomyocytes, hepatocytes and neurons. Its role in renal I/R is unknown. We investigated the impact ... [more ▼]

Activation of the calcium-sensing receptor (CaSR) by ischemia/reperfusion (I/R) favours apoptosis in cardiomyocytes, hepatocytes and neurons. Its role in renal I/R is unknown. We investigated the impact of pharmacological preactivation of the CaSR on kidney structure and function in a murine model of bilateral renal 30-min ischemia and 48-hour reperfusion, and in a 6-year cohort of kidney transplant recipients (KTR). C57BL/6J mice were administered daily with CaSR agonist, R-568, or with vehicle for 48 hours. Evaluation of serum urea and creatinine levels, renal histology and urine metabolome by nuclear magnetic resonance showed that R-568 was not nephrotoxic per se. Following I/R, serum urea and creatinine levels increased higher in R-568-treated animals than in controls. Jablonski’s score was significantly greater in R-568-treated kidneys, which showed a higher rate of cell proliferation and apoptosis in comparison to controls. Next, we retrospectively identified 36 patients (10.7% of our cohort) who were treated by CaSR agonist, cinacalcet, at the time of kidney transplantation (KTx). After matching these to 61 KTR upon type of donor, cold ischemic time, residual diuresis, and donor age, we observed that delayed graft function, i.e. need for dialysis in the first week after KTx, occurred in 42 and 23% of cinacalcet-treated and control groups, respectively (p≤0.05). These data suggest that pharmacological preactivation of the CaSR before renal I/R exacerbates kidney injury. [less ▲]

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