Bone morphogenetic protein-5 and early endothelial outgrowth cells (eEOCs) in acute ischemic kidney injury (AKI) and 5/6-chronic kidney disease

Abstract

Early endothelial outgrowth cells (eEOCs) reproducibly have been shown to act protectively in acute ischemic kidney injury (AKI) and chronic kidney injury. Bone morphogenetic protein-5 (BMP-5) acted antifibrotically in human hypertensive nephropathy. The aim of the current study was to analyze effects of BMP-5 treatment in an eEOC-based therapy of murine AKI and 5/6-nephrectomy. Male C57/Bl6N mice were either subjected to unilateral renal artery clamping postuninephrectomy or to 5/6-nephrectomy. Untreated or BMP-5-pretreated murine eEOCs were injected into recipient animals at the time of reperfusion (AKI) or at 2 and 5 days after 5/6-nephrectomy. Analysis of renal function and morphology was performed at 48 h and at 6 wk (AKI) or at 8 wk (5/6 model). Cellular consequences of eEOC treatment were evaluated using different in vitro assays. AKI was mitigated significantly by injecting BMP-5-pretreated eEOCs. Renal function was improved at 48 h [corrected] after cell therapy. In 5/6-nephrectomy, the cells failed to act renoprotectively, [corrected] but proteinuria was reduced after administering untreated eEOCs." Next, the original version read as "BMP-5 acts as a potent eEOC agonist in murine AKI in the short [corrected] term. Cell effects in 5/6-nephrectomy are heterogenous, but untreated cells act antifibrotically [corrected] without any impact on EnMT.

Angiopoietin-1 treated early endothelial outgrowth cells (eEOCs) are activated in vitro and reduce renal damage in murine acute ischemic kidney injury (iAKI)

“…The hormone melatonin improved antiischemic actions of eEOCs in AKI as well [23]. Recently, the protein BMP-5 was identified as another eEOC agonist in this situation [27]. Thus, Early Endothelial Outgrowth Cells increasingly become a therapeutic option in ischemic AKI.…”

“…Angiopoietin-1 plays a crucial role in maintaining vascular homeostasis under physiological conditions and this study undoubtedly proves an eEOC-agonistic role of the protein in iAKi although it still remains to be elucidated which excact mechanisms promote eEOC renoprotection in vivo. At this point, several endogenous [25] and exogenous agonists of eEOCs have been identified (8-O-cAMP, Melatonin, BMP-5, Ang-1 [23,24,27]). A first study on therapeutic administration of eEOCs in human AKI is being planned at the moment.…”

Cell-Based Therapies in Acute Kidney Injury (AKI)

“…Both subpopulations, PACs and ECFCs have sucessfully been administered in experimental AKI [44-48]. In addition, several strategies have been established in order to augment AKI-protective effects of particularly PACs [46, 47, 49-51]. In almost all of the mentioned studies, kidney excretory function was evaluated by serum creatinine levels and additionally by certain morphological parameters such as acute tubular damage shortly (48 hours) after ischemia.…”

“…Thus, further studies were intended to augment the AKI-protective capacity of PACs and several pharmacological agonists of the cells were identified. Among those were melatonin [47], 8-O-cAMP [51], Bone Morphogenetic Protein-5 (BMP-5) [46], and Angiopoietin-1 [50] and -2 [49]. A more recent study showed that PACs administration post-AKI did not only prevent the kidney from acute loss of excretory function but also stabilizeed certain structural outcome parameters such as interstitial fibrosis and loss of peritubular capillaries [52].…”

PAC-mediated AKI protection is critically mediated but does not exclusively depend on cell-derived microvesicles

“…Both components were either isolated from native cells or from stimulated PACs. Since previous own studies showed substantial PAC agonistic effects of Angiopoietin-1 / -2 [15,16], Bone Morphogenetic Protein-5 [17], and Melatonin [8], we decided to utilize each of these four mediators in an individual series of experiments. Therefore, we performed a total number of 15 interventional groups.…”