Human mesenchymal stromal cells ameliorate complement induced inflammatory cascade and improve renal functions in a rat model of ischemia-reperfusion induced acute kidney injury

Abstract

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.

Mesenchymal Stromal Cell Uses for Acute Kidney Injury—Current Available Data and Future Perspectives: A Mini-Review

“…An increase in the M2 macrophage CD68/CD163 population. As discussed, these M2 macrophages have anti-inflammatory and proregenerative properties ( 28 , 32 ).…”

“…Following IRI, MSCs migrate to the injured site and alleviate the damage ( 21 ). Studies have demonstrated that MSCs have beneficial effects even at very early stages after their migration, before any differentiation and proliferation can be expected ( 28 ). This observation has led to the understanding that the MSC's early beneficial effects are related to their paracrine activity in the surrounding tissue ( 29 , 30 ).…”

“…An inhibitory effect on the complement system's overactivation and the related cellular damage generated by the membrane attack complex ( 28 ).…”

“…The first concern is related to the administration technique. When the cells are administered intravenously (IV), most of the cells are found within the lungs ( 28 , 64 ). When the lung capillaries are blocked with these cells, ventilation, and respiratory difficulties ensue.…”

Rats with congenital hydronephrosis show increased susceptibility to renal ischemia‐reperfusion injury

“…Excluding hydronephrotic animals would be very important if the unilateral renal I-R model with the removal of contralateral kidney is exploited. Researchers have performed the above-mentioned experimental model by removing the right (Zilberman-Itskovich et al, 2019) or left (Ar'Rajab et al, 1994) kidney. As the right-sided F I G U R E 5 Effects of unilateral hydronephrosis on the L-carnitine (a) and furosemide (b) concentrations in the plasma after a single subcutaneous administration.…”