Abstract
Abstract Background and Aims Acute Kidney Injury (AKI) significantly worsens the prognosis of hospitalized patients. In recent years, cell-based strategies have been established as reliable option for improving AKI outcomes in experimental AKI. Own studies focused on so-called Proangiogenic Cells (PACs). Mechanisms that contribute to PAC-mediated AKI protection include production / secretion of extracellular vesicles (EV). In addition, the cells most likely act by paracrinic processes (secretome). The current study evaluated whether AKI may be preventable by the administration of either PAC-derived EV and / or the secretome alone. Method AKI was induced in male C57/Bl6N mice (8-12 weeks) by bilateral renal ischemia (IRI - 40 minutes). Syngeneic murine PACs were stimulated with either melatonine, Angiopoietin-1 or -2, or with Bone Morphogenetic Protein-5 (BMP-5) for one hour, respectively. The four mediators were chosen since previous own studies showed improved PAC-mediated AKI protection after cell preconditioning with these substances. PAC-derived EV and the vesicle-depleted supernatant were subsequently collected and i.v. injected post-ischemia. Mice were analyzed 48 hours later. Results IRI induced significant kidney excretory dysfunction as reflected by higher serum cystatin C levels. The only measure that improved AKI was the injection of EV, collected from native PACs. The following conditions worsened post-ischemic renal function even further: EV+Ang-1, EV+BMP-5, EV+melatonin, and EV+secretome+Ang-1. Conclusion Together, our data show that PAC-mediated AKI protection substantially depends on the availability of cell-derived EV. The secretome, either collected from native or preconditioned cells does not prevent mice from ischemia-induced dysfunction. However, since previous data showed improved AKI-protection by PACs after cell preconditioning with certain mediators (Ang-1 and -2, melatonine, BMP-5), other than exclusively vesicle-dependent mechanisms must be involved in PAC-mediated AKI protection. We suggest, that the mere presence of intact cells in the post-ischemic tissue is necessary for improving functional and structural outcome parameters under certain conditions.
Highlights
Acute kidney injury (AKI) significantly worsens the prognosis of hospitalized patients
Several other investigations focused on proangiogenic cells (PACs), which for many years were defined as early endothelial progenitor cells [7]
AKI worsens the prognosis of respective subjects in the short and in the long term. e long-term prognosis critically depends on AKI-associated vascular rarefaction and interstitial fibrosis. e pathogenesis of latter is complex
Summary
In-hospital incidences of AKI (Acute Kidney Injury) have been increased over the last 10–15 years. Cell-derived therapies have been utilized in experimental AKI; the results are promising. Ere are certain problems associated with cell-based therapies in AKI in general. In 2012, Cantaluppi and colleagues [10] identified cell-derived microvesicles (MV) to be of critical importance for AKI protection. Since the study by Cantaluppi, numerous other investigators reported on kidney-protective roles of certain types of extracellular vesicles, derived from heterogenous cell types such as mesenchymal stem cells, endothelial colony forming cells, induced pluripotent stem cells, and others [11,12,13,14,15,16,17,18] (Bruno, Zhou, Herrera, Collina, Burger, Zhang, Ranghino, Yuan). Cell-derived vesicles have been accepted as mediators of tissue protection under various circumstances.
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