The current study examined the role of Na/K-ATPase α1-subunit in animals subjected to 5/6th partial nephrectomy (PNx) using Na/K-ATPase α1-heterozygous (α1(+/-)) mice and their wild-type (WT) littermates. After PNx, both WT and α1(+/-) animals displayed diastolic dimension increases, increased blood pressure, and increased cardiac hypertrophy. However, in the α1(+/-) animals we detected significant increases in cardiac cell death in PNx animals. Given that reduction of α1 elicited increased cardiac cell death with PNx, while at the same time these animals developed cardiac hypertrophy, an examination of cardiac cell number, and proliferative capabilities of those cells was carried out. Cardiac tissues were probed for the progenitor cell marker c-kit and the proliferation marker ki-67. The results revealed that α1(+/-) mice had significantly higher numbers of c-kit-positive and ki-67-positive cells, especially in the PNx group. We also found that α1(+/-) mice express higher levels of stem cell factor, a c-kit ligand, in their heart tissue and had higher circulating levels of stem cell factor than WT animals. In addition, PNx induced significant enlargement of cardiac myocytes in WT mice but has much less effect in α1(+/-) mice. However, the total cell number determined by nuclear counting is higher in α1(+/-) mice with PNx compared with WT mice. We conclude that PNx induces hypertrophic growth and high blood pressure regardless of Na/K-ATPase content change. However, total cardiac cell number as well as c-kit-positive cell number is increased in α1(+/-) mice with PNx.

Endogenous ligands of Na/K-ATPase have been demonstrated to increase in kidney dysfunction and heart failure. It is also reported that Na/K-ATPase signaling function effects stem cell differentiation. This study evaluated whether Na/K-ATPase activation through its ligands and associated signaling functions affect bone marrow stromal cells (BMSCs, also known as bone marrow-derived mesenchymal stem cells) differentiation capacity. BMSCs were isolated from male Sprague-Dawley rats and cultured in minimal essential medium alpha (MEM-α) supplemented with 15% Fetal Bovine serum (FBS). The results showed that marinobufagenin (MBG), a specific Na/K-ATPase ligand, potentiated rosiglitazone-induced adipogenesis in these BMSCs. Meanwhile, it attenuated BMSCs osteogenesis. Mechanistically, MBG increased CCAAT/enhancer binding protein alpha (C/EBPα) protein expression through activation of an extracellular regulated kinase (ERK) signaling pathway, which leads to enhanced rosiglitazone-induced adipogenesis. Inhibition of ERK activation by U0126 blocks the effect of MBG on C/EBPα expression and on rosiglitazone-induced adipogenesis. Reciprocally, MBG reduced runt-related transcription factor 2 (RunX2) expression, which resulted in the inhibition of osteogenesis induced by β-glycerophosphate/ascorbic acid. MBG also potentiated rosiglitazone-induced adipogenesis in 3T3-L1 cells and in mouse BMSCs. These results suggest that Na/K-ATPase and its signaling functions are involved in the regulation of BMSCs differentiation.

Objective This review will focus on serotonin transporter gene (5-HTTLP), Na/K ATPase isoforms, Fat-mass and obesity-associated gene (FTO) and mTOR signaling pathway. Methods PubMed, Scopus and Google scholar database was the primary source to search with relevant key words. The search included all English-language papers published since 1974. Results Across the studies analyzed in this review, the association between obesity and depression is still controversial. With some emerging data pointing at a clear relationship between the two, however, others may claim the opposite. Starting with metabolism and nutrients uptake and moving to energy production, it seems that sodium pump and its different isoforms could be a partner with serotonin whether it leads to alteration in BMI or fluctuation in mood and behavior. The rising role of FTO in both obesity and depression with the exciting data that shows how mTOR pathway could be regulating its function, sodium pump once again could have a role in this play. Conclusion To sum up, it is still not clear how these three genes could be connected to each other, but looks like they deserve more focus in future research endeavors.

Bone‐marrow derived stromal cells (BMSCs) have the capacity to differentiate multi‐directionally. We have demonstrated that the signaling function of Na/K‐ATPase plays an important role in regulating cell survival and cell growth. This study is to test if Na/K‐ATPase and its signaling functions affect BMSCs survival and differentiation capacity. BMSCs isolated from Sprauge‐Dawley male rats were cultured in α‐MEM containing 15% FBS. The purified third generation of BMSCs was treated with 10nM or 1μM marinobufagenin (MBG, a cardiotonic steroid) for 72h then the cells were induced to differentiate into adipocytes or osteoblasts using 1μM Rosiglitazone or 10mM β‐glycerophosphate, respectively. The results illustrated that MBG treatment activates the Na/K‐ATPase signaling pathway and promoted Rosiglitazone‐induced adipogenesis. In addition, MBG treatment resulted in a trend of decreased osteogenesis induced by β‐glycerophosphate, but not in a statistically significant manner. To evaluate the mechanism behind this phenomenon, BMSCs were pretreated with 1μM PP2 (a Src inhibitor) for 30 minutes, then cells were treated with 10nM and 1μM MBG for 72 hours before the induction of adipogenesis. This combined treatment decreased adipogenesis when compared to cells treated with MBG alone. These results suggest Na/K‐ATPase and its signaling functions are involved in the regulation of BMSCs differentiation. Supported by NIH HL‐105649