It has been reported that uremic conditions cause

It has been reported that uremic conditions cause defects in BMSC self-renewal and differentiation (He et al., 2009; Noh et al., 2012). Our previous studies showed that chronic kidney disease induced by partial nephrectomy (PNx) increases the circulating level of Na/K-ATPase ligands in rat and mouse models (Kennedy et al., 2006, 2008). Na/K-ATPase ligands are a group of digitalis-like compounds, including plant-derived digitalis drugs such as digoxin and ouabain, and vertebrate-derived aglycones such as bufalin and marinobufagenin (MBG) (Akera and Brody, 1976; Barry et al., 1985; Schoner, 2002). These compounds were also found to be released endogenously, known as cardiotonic steroids (CTS), in animals and humans with essential hypertension, heart failure and renal dysfunction (Balzan et al., 2001; Fridman et al., 2002; Gottlieb et al., 1992; Manunta et al., 1999; Tian et al., 2010). The production and secretion of CTS are regulated by multiple physiological stimuli including ACTH and angiotensin II (Fedorova et al., 1998; Hamlyn et al., 1991; Laredo et al., 1997; Schoner, 2002). High levels of circulating CTS are an important risk factor that contributes to uremia-induced cardiac remodeling and dysfunction (Bagrov et al., 2009; Palazzuoli and Ronco, 2011; Simoes and Flynn, 2012). Mechanistically, a role for Na/K-ATPase ligand-induced signaling has been demonstrated in the regulation of somatic cell growth and survival (Liu et al., 2012; Tian et al., 2009). However, the effects of these compounds on BMSCs differentiation are not well studied. Previous reports demonstrated Na/K-ATPase expression in undifferentiated embryonic stem Protease Inhibitor Library (ESCs) as well as in ESC-derived cardiomyocytes (Otsu et al., 2005). CTS such as ouabain promote differentiation of ESCs into cardiac myocytes through an extracellular regulated kinase (ERK) signaling pathway (Lee et al., 2011). This study evaluated whether CTS-induced Na/K-ATPase signaling regulates differentiation in BMSCs.
Materials and methods
Results
Discussion The current study demonstrated the involvement of Na/K-ATPase and its ligands in stem cell differentiation, which has not been well studied in the field. Na/K-ATPase is an important membrane ion transporter existing in all mammalian cells. The function of Na/K-ATPase lies in two aspects, namely the ion transporting function and signal transducing function (Aizman and Aperia, 2003; Tian et al., 2006; Xie and Cai, 2003). The physiologic and pathologic role of Na/K-ATPase has been well studied in somatic cells such as kidney and heart cells, showing that activation of Na/K-ATPase signaling can induce cardiac hypertrophy, fibrosis, and regulate cell apoptosis under different conditions (Kennedy et al., 2006, 2008; Li et al., 2006; Liu et al., 2012; Tian et al., 2009). Only recently has the research on the effect of Na/K-ATPase in stem cell differentiation been initiated. It was reported that ouabain, another specific ligand of Na/K-ATPase, facilitates cardiac differentiation of embryonic stem cells via activation of an ERK-regulated signaling pathway (Lee et al., 2011); it also affects BMSCs differentiation by regulating the membrane potential (Sundelacruz et al., 2008). In addition to Na/K-ATPase, other ion transporting proteins such as, Ca-activated K+ channels (BKKCa) (Zhang et al., 2014), voltage sensitive K+ channels (You et al., 2013) and H+-pump (Adams et al., 2007) have been reported to regulate stem cell development and differentiation. These findings together with our current data suggest that ion transporters, traditionally considered as essential components for maintaining the homeostasis of ion concentration and electrical charge, may actually also participate in regulating cell signaling process including stem cell differentiation. However, whether the regulation is through the ion flow or signaling pathway or both remains elusive and merits further studies.