IntroductionThe primary rational for using mesenchymal stromal cells (MSCs) to rejuvenate damaged tissue is mostly based on their capacity to trans-differentiate and repair injured organs. However, previous studies have demonstrated that MSCs are beneficial even at very early stages, before differentiation and proliferation can be expected. The aim of the current study was to investigate the multifaceted immunological effects of systemically administrating MSCs in the setting of acute kidney injury (AKI) induced by ischemic-reperfusion (I/R).MethodsA rat model of I/R induced AKI was used. The rats underwent a unilateral nephrectomy with simultaneously clamping the contralateral kidney for 60 minutes. Four treatment groups received intravenously, increasing doses of human MSCs and after 48 hours, the rats were sacrificed. Blood was taken to evaluate renal functions and to measure systemic inflammatory markers. Kidneys were taken for histopathologic examinations and evaluations of intra-renal complement activation and inflammatory mediators.ResultsRenal functions improved in U shaped dose dependent manner. Mean serum creatinine levels were 4.5, 2.9, 2.6, 1.7 and 4.1 mg/dL in I/R + placebo, I/R + 150x103 cells, I/R + 250x103 cells, I/R + 500x103 cells and I/R + 1,000x103 cells respectfully (p-values<0.05). Urea demonstrated consistent results with the same U shape improvement manner. The extensive activation of the complement system was ameliorated in the MSCs treatment groups. In addition, MSCs significantly decreased intra-renal levels of IL-1β and TNF-α. It should be noted that the highest doses of MSCs induced renal hypoxia, marked by the Hypoxy-probe staining.ConclusionsThe early beneficial effect of MSCs in the setting of AKI may be attributed to their immunomodulatory effects. Safe treatment with MSCs can block the deleterious activation of the complement cascade and alleviate the hazardous inflammatory mediator-related cascade.

Aim: The complement system is activated in acute kidney injury (AKI). Anti-C5 antibody targets the common terminal portion of the complement cascade that generate the terminal complex C5b-9 and has a renal-protective effect in paroxysmal nocturnal hemoglobinuria. However, the anti-C5 antibody’s role in ischemia/reperfusion (I/R)-induced AKI has not been fully investigated. We therefore evaluated its effect on the pathophysiological cascade of I/R-induced AKI.Methods: Sprague–Dawley rats underwent unilateral right kidney nephrectomies with simultaneous clamping of the contralateral hilum for 60 min (ischemia), followed by reperfusion. In addition to a placebo, two treatment groups received either high or low doses of anti-C5 monoclonal antibody. After 48 h, the rats were euthanized, blood was drawn to evaluate systemic inflammation and to estimate glomerular filtration rate (GFR). The remaining kidney was removed for pathological evaluation and intra-renal complement activation.Results: I/R induced significant intra-renal complement activation and systemic inflammation compared with unilateral nephrectomy group. The anti-C5 antibody ameliorated the intra-renal complement activation (intra-renal C3 and C6), reduced systemic inflammation (C-reactive protein, and systemic C3), decreased intra-renal acute tubular necrosis damage and improved GFR (seen by the sensitive marker, serum cystatin C; 1.63 mg/L (I/R + placebo), 1.36 mg/L (I/R + low dose) and 1.21 mg/L (I/R + high dose), p = .08 and .03 compared with I/R + placebo).Conclusion: In I/R-induced AKI, the monoclonal anti-C5 complement factor ameliorates intra renal complement activation, decreases local and systemic inflammation and may improve GFR.

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BackgroundRegulation of hepatic glucose production has been a target for antidiabetic drug development, due to its major contribution to glucose homeostasis. Previous pre-clinical study demonstrated that peripheral electrical stimulation (PES) may stimulate glucose utilization and improve hepatic insulin sensitivity. The aim of the present study was to evaluate safety, tolerability, and the glucose-lowering effect of this approach in patients with type 2 diabetes (T2DM).MethodsTwelve patients with T2DM were recruited for an open label, interventional, randomized trial. Eleven patients underwent, in a crossover design, an active, and a no-intervention control periods, separated with a two-week washout phase. During the active period, the patients received a daily lower extremity PES treatment (1.33Hz/16Hz burst mode), for 14 days. Study endpoints included changes in glucose levels, number of hypoglycemic episodes, and other potential side effects. Endpoints were analyzed based on continuous glucose meter readings, and laboratory evaluation.ResultsWe found that during the active period, the most significant effect was on nocturnal glucose control (P < 0.0004), as well as on pre-meal mean glucose levels (P < 0.02). The mean daily glucose levels were also decreased although it did not reach clinical significance (P = 0.07). A reduction in serum cortisol (P < 0.01) but not in insulin was also detected after 2 weeks of treatment. No adverse events were recorded.ConclusionsThese results indicate that repeated PES treatment, even for a very short duration, can improve blood glucose control, possibly by suppressing hepatic glucose production. This effect may be mediated via hypothalamic-pituitary-adrenal axis modulation.Trial registrationClinicalTrials.gov NCT02727790