Abstract
BackgroundRenal ischemia–reperfusion (I/R) injury is a major cause of acute kidney injury (AKI), which is associated with high morbidity and mortality. AKI is a serious and costly medical condition. Effective therapy for AKI is an unmet clinical need, and molecular mechanisms underlying the interactions between an injured kidney and distant organs remain unclear. Therefore, novel therapeutic strategies should be developed.MethodsWe directed the differentiation of human induced pluripotent stem (iPS) cells into endothelial progenitor cells (iEPCs), which were then applied for treating mouse AKI. The mouse model of AKI was induced by I/R injury.ResultsWe discovered that intravenously infused iEPCs were recruited to the injured kidney, expressed the mature endothelial cell marker CD31, and replaced injured endothelial cells. Moreover, infused iEPCs produced abundant proangiogenic proteins, which entered into circulation. In AKI mice, blood urea nitrogen and plasma creatinine levels increased 2 days after I/R injury and reduced after the infusion of iEPCs. Tubular injury, cell apoptosis, and peritubular capillary rarefaction in injured kidneys were attenuated accordingly. In the AKI mice, iEPC therapy also ameliorated apoptosis of cardiomyocytes and cardiac dysfunction, as indicated by echocardiography. The therapy also ameliorated an increase in serum brain natriuretic peptide. Regarding the relevant mechanisms, indoxyl sulfate and interleukin-1β synergistically induced apoptosis of cardiomyocytes. Systemic iEPC therapy downregulated the proapoptotic protein caspase-3 and upregulated the anti-apoptotic protein Bcl-2 in the hearts of the AKI mice, possibly through the reduction of indoxyl sulfate and interleukin-1β.ConclusionsTherapy using human iPS cell-derived iEPCs provided a protective effect against ischemic AKI and remote cardiac dysfunction through the repair of endothelial cells and the attenuation of cardiomyocyte apoptosis.
Highlights
Renal ischemia–reperfusion (I/R) injury is a major cause of acute kidney injury (AKI), which is associated with high morbidity and mortality
Inspired by the aforementioned previous study, we considered whether therapy using iPS cell-derived endothelial progenitor cells (iEPCs) would result in protective effects in a mouse model of AKI induced by ischemia–reperfusion (I/R) injury
We confirmed that acetylated low-density lipoprotein was taken up by iEPCs but not by induced pluripotent stem (iPS) cells (Additional file 1: Figure S1e and f )
Summary
Renal ischemia–reperfusion (I/R) injury is a major cause of acute kidney injury (AKI), which is associated with high morbidity and mortality. Despite the availability of renal replacement therapy, AKI is associated with high mortality and morbidity [2,3,4,5]. Clinical evidence suggests that AKI is an indicator of illness severity but that it leads to distant-organ injury and considerably affects mortality [6,7,8,9,10]. A recent study further demonstrated that AKI may activate the production of dynamin-related protein 1 (Drp1) and may induce mitochondrial fragmentation in cardiomyocytes, thereby leading to cell apoptosis and cardiac dysfunction. Drp has become a new therapeutic target to alleviate AKI-induced cardiac dysfunction [10]
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