The hormone melatonin stimulates renoprotective effects of “early outgrowth” endothelial progenitor cells in acute ischemic kidney injury

Abstract

Endothelial progenitor cells (EPCs) protect the kidney from acute ischemic injury. The aim of this study was to analyze whether pretreatment of murine "early outgrowth" EPCs (eEPCs) with the hormone melatonin increases the cells' renoprotective effects in the setting of murine acute ischemic renal failure. Male (8-12 wk old) C57Bl/6N mice were subjected to unilateral ischemia-reperfusion injury postuninephrectomy (40 min). Postischemic animals were injected with either 0.5×10(6) untreated syngeneic murine eEPCs or with cells, pretreated with melatonin for 1 h. Injections were performed shortly after reperfusion of the kidney. While animals injected with untreated cells developed acute renal failure, eEPC pretreatment with melatonin dramatically improved renoprotective actions of the cells. These effects were completely reversed after cell pretreatment with melatonin and the MT-1/-2 antagonist luzindole. In vitro analysis revealed that melatonin reduced the amount of tumor growth factor-β-induced eEPC apoptosis/necrosis. Secretion of vascular endothelial growth factor by the cells was markedly stimulated by the hormone. In addition, migratory activity of eEPCs was enhanced by melatonin and supernatant from melatonin-treated eEPCs stimulated migration of cultured mature endothelial cells. In summary, melatonin was identified as a new agonist of eEPCs in acute ischemic kidney injury.

Melatonin pretreatment of human adipose tissue-derived mesenchymal stromal cells enhances their prosurvival and protective effects on human kidney cells

“…A recent study demonstrated that melatonin pretreatment of murine "early outgrowth" endothelial progenitor cells (eEPCs) enhanced the protective actions of these cells in mice with acute ischemic kidney damage (32), and that these effects were reversed when cells were instead cotreated with a melatonin receptor antagonist and melatonin. Furthermore, the authors observed in vitro that these eEPCs had a higher migratory ability when pretreated with melatonin (32). Also, they showed that melatonin could protect against apoptosis/necrosis induced by transforming growth factor-␤.…”

“…Also, they showed that melatonin could protect against apoptosis/necrosis induced by transforming growth factor-␤. These authors referred to melatonin as a new agonist of EPCs in acute ischemic kidney injury (32).…”

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].…”

Simvastatin attenuates TNF-α-induced apoptosis in endothelial progenitor cells via the upregulation of SIRT1

“…In this manner, they participate in the repair of damaged tissues, thereby improving blood flow and attenuating the progression of atherosclerosis (1). Since both animal models and human studies have shown that EPCs can contribute to neovascularization and re-endothelialization, EPCs have been examined as potential treatments for various types of ischemic disease, including stroke (2), ischemic myocardium (3,4), kidney injury (5), and ischemic vascular disease (6). Moreover, it has been reported that a low EPC level is an independent risk factor for future cardiovascular events such as unstable angina and myocardial infarction (MI) (7,8).…”