Proinflammatory Effects of Cardiotonic Steroids Mediated by NKA α-1 (Na+/K+-ATPase α-1)/Src Complex in Renal Epithelial Cells and Immune Cells.

Cardiotonic steroids (CTSs) are NKA α-1 (Na/K-ATPase α-1) ligands that are increased in volume expanded states and associated with cardiac and renal diseases. Although initiation and resolution of inflammation is an important component of cellular injury and repair in renal disease, it is unknown whether CTS activation of NKA α-1 signaling in this setting regulates this inflammatory response. On this background, we hypothesized that CTS signaling through the NKA α-1-Src kinase complex promotes a proinflammatory response in renal epithelial and immune cells.

Characterization of a Long Non-Coding RNA, the Antisense RNA of Na/K-ATPase α1 in Human Kidney Cells.

Non-coding RNAs are important regulators of protein-coding genes. The current study characterized an antisense long non-coding RNA, , which is located on the opposite strand of the Na/K-ATPase α1 gene. Our results show that four splice variants are expressed in human adult kidney cells (HK2 cells) and embryonic kidney cells (HEK293 cells).

A computerized exposure system for animal models to optimize nicotine delivery into the brain through inhalation of electronic cigarette vapors or cigarette smoke.

Pre-clinical studies investigated the effects of chronic exposure to nicotine on lungs, kidneys and brains using animal models. Most of these studies delivered nicotine into the circulatory and central nervous systems (CNS) through intraperitoneal injection or oral consumption methods. Few studies used inhalation machine system for nicotine delivery into brains in rodents to mimic human exposure to cigarettes.

Na/K-ATPase signaling mediates miR-29b-3p regulation and cardiac fibrosis formation in mice with chronic kidney disease.

The Na/K-ATPase is an important membrane ion transporter and a signaling receptor that is essential for maintaining normal cell function. The current study examined the role of Na/K-ATPase signaling in regulating miR-29b-3p, an anti-fibrotic microRNA, in a mouse chronic kidney disease (CKD) model (5/6th partial nephrectomy or PNx). The results showed that CKD induced significant reduction of miR-29b-3p expression in the heart tissue by activation of Src and NFκB signaling in these animals.

Chronic inhalation of e-cigarette vapor containing nicotine disrupts airway barrier function and induces systemic inflammation and multiorgan fibrosis in mice.

Electronic (e)-cigarettes theoretically may be safer than conventional tobacco. However, our prior studies demonstrated direct adverse effects of e-cigarette vapor (EV) on airway cells, including decreased viability and function. We hypothesize that repetitive, chronic inhalation of EV will diminish airway barrier function, leading to inflammatory protein release into circulation, creating a systemic inflammatory state, ultimately leading to distant organ injury and dysfunction.

Corrigendum: Attenuation of Na/K-ATPase Mediated Oxidant Amplification with pNaKtide Ameliorates Experimental Uremic Cardiomyopathy.

This corrects the article DOI: 10.1038/srep34592.

MicroRNA profiling in kidney disease: Plasma versus plasma-derived exosomes.

Liquid biopsies have advanced rapidly in recent years for use in diagnostic and prognostic applications. One important aspect of this advancement is the growth in our understanding of microRNA (miRNA) biology. The measurement of miRNAs packaged within exosomes, which are constantly released into the blood stream, may reflect pathological changes within the body.

Effects of chronic inhalation of electronic cigarettes containing nicotine on glial glutamate transporters and α-7 nicotinic acetylcholine receptor in female CD-1 mice.

Alteration in glutamate neurotransmission has been found to mediate the development of drug dependence, including nicotine. We and others, through using western blotting, have reported that exposure to drugs of abuse reduced the expression of glutamate transporter-1 (GLT-1) as well as cystine/glutamate antiporter (xCT), which consequently increased extracellular glutamate concentrations in the mesocorticolimbic area. However, our previous studies did not reveal any changes in glutamate/aspartate transporter (GLAST) following exposure to drugs of abuse.

Sodium potassium adenosine triphosphatase (Na/K-ATPase) as a therapeutic target for uremic cardiomyopathy.

Clinically, patients with significant reductions in renal function present with cardiovascular dysfunction typically termed, uremic cardiomyopathy. It is a progressive series of cardiac pathophysiological changes, including left ventricular diastolic dysfunction and hypertrophy (LVH) which sometimes progress to left ventricular dilation (LVD) and systolic dysfunction in the setting of chronic kidney disease (CKD). Uremic cardiomyopathy is almost ubiquitous in patients afflicted with end stage renal disease (ESRD).

Cigarette smoking and cardio-renal events in patients with atherosclerotic renal artery stenosis.

Cigarette smoking causes cardiovascular disease and is associated with poor kidney function in individuals with diabetes mellitus and primary kidney diseases. However, the association of smoking on patients with atherosclerotic renal artery stenosis has not been studied. The current study utilized data from the Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL, NCT00081731) clinical trial to evaluate the effects of smoking on the risk of cardio-renal events and kidney function in this population.

An alternative empirical likelihood method in missing response problems and causal inference.

Missing responses are common problems in medical, social, and economic studies. When responses are missing at random, a complete case data analysis may result in biases. A popular debias method is inverse probability weighting proposed by Horvitz and Thompson.

Cigarette smoking causes epigenetic changes associated with cardiorenal fibrosis.

Clinical studies indicate that smoking combustible cigarettes promotes progression of renal and cardiac injury, leading to functional decline in the setting of chronic kidney disease (CKD). However, basic studies using in vivo small animal models that mimic clinical pathology of CKD are lacking. To address this issue, we evaluated renal and cardiac injury progression and functional changes induced by 4 wk of daily combustible cigarette smoke exposure in the 5/6th partial nephrectomy (PNx) CKD model.

Attenuation of Na/K-ATPase Mediated Oxidant Amplification with pNaKtide Ameliorates Experimental Uremic Cardiomyopathy.

We have previously reported that the sodium potassium adenosine triphosphatase (Na/K-ATPase) can effect the amplification of reactive oxygen species. In this study, we examined whether attenuation of oxidant stress by antagonism of Na/K-ATPase oxidant amplification might ameliorate experimental uremic cardiomyopathy induced by partial nephrectomy (PNx). PNx induced the development of cardiac morphological and biochemical changes consistent with human uremic cardiomyopathy.

Rapamycin Attenuates Cardiac Fibrosis in Experimental Uremic Cardiomyopathy by Reducing Marinobufagenin Levels and Inhibiting Downstream Pro-Fibrotic Signaling.

Background: Experimental uremic cardiomyopathy causes cardiac fibrosis and is causally related to the increased circulating levels of the cardiotonic steroid, marinobufagenin (MBG), which signals through Na/K-ATPase. Rapamycin is an inhibitor of the serine/threonine kinase mammalian target of rapamycin (mTOR) implicated in the progression of many different forms of renal disease. Given that Na/K-ATPase signaling is known to stimulate the mTOR system, we speculated that the ameliorative effects of rapamycin might influence this pathway.

Targeted disruption of Cd40 in a genetically hypertensive rat model attenuates renal fibrosis and proteinuria, independent of blood pressure.

High blood pressure is a common cause of chronic kidney disease. Because CD40, a member of the tumor necrosis factor receptor family, has been linked to the progression of kidney disease in ischemic nephropathy, we studied the role of Cd40 in the development of hypertensive renal disease. The Cd40 gene was mutated in the Dahl S genetically hypertensive rat with renal disease by targeted-gene disruption using zinc-finger nuclease technology.

Protein Carbonylation of an Amino Acid Residue of the Na/K-ATPase α1 Subunit Determines Na/K-ATPase Signaling and Sodium Transport in Renal Proximal Tubular Cells.

Background: We have demonstrated that cardiotonic steroids, such as ouabain, signaling through the Na/K-ATPase, regulate sodium reabsorption in the renal proximal tubule. By direct carbonylation modification of the Pro222 residue in the actuator (A) domain of pig Na/K-ATPase α1 subunit, reactive oxygen species are required for ouabain-stimulated Na/K-ATPase/c-Src signaling and subsequent regulation of active transepithelial (22)Na(+) transport. In the present study we sought to determine the functional role of Pro222 carbonylation in Na/K-ATPase signaling and sodium handling.

Hiding inside? Intracellular expression of non-glycosylated c-kit protein in cardiac progenitor cells.

Cardiac progenitor cells including c-kit(+) cells and cardiosphere-derived cells (CDCs) play important roles in cardiac repair and regeneration. CDCs were reported to contain only small subpopulations of c-kit(+) cells and recent publications suggested that depletion of the c-kit(+) subpopulation of cells has no effect on regenerative properties of CDCs. However, our current study showed that the vast majority of CDCs from murine heart actually express c-kit, albeit, in an intracellular and non-glycosylated form.

Na/K-ATPase signaling regulates collagen synthesis through microRNA-29b-3p in cardiac fibroblasts.

Chronic kidney disease (CKD) is accompanied by cardiac fibrosis, hypertrophy, and dysfunction, which are commonly referred to as uremic cardiomyopathy. Our previous studies found that Na/K-ATPase ligands or 5/6th partial nephrectomy (PNx) induces cardiac fibrosis in rats and mice. The current study used in vitro and in vivo models to explore novel roles for microRNA in this mechanism of cardiac fibrosis formation.

Endovascular versus medical therapy for atherosclerotic renovascular disease.

The diagnosis of renal artery stenosis (RAS) has become increasingly common in part due to greater awareness of ischemic renal disease and increased use of diagnostic techniques. Over 90 % of RAS cases are caused by atherosclerotic renovascular disease (ARVD). Patients with ARVD are at high risk for fatal and nonfatal cardiovascular and renal events.

Effects of Na/K-ATPase and its ligands on bone marrow stromal cell differentiation.

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.

Reduction of Na/K-ATPase affects cardiac remodeling and increases c-kit cell abundance in partial nephrectomized mice.

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.

Gender differences in the development of uremic cardiomyopathy following partial nephrectomy: Role of progesterone.

Gender difference has been suggested as a risk factor for developing cardiovascular and renal diseases in humans and experimental animals. As a major sex hormone, progesterone was reported to compete with cardiotonic steroid binding to Na/K-ATPase. Our previous publication demonstrated that cardiotonic steroids (e.

Mechanisms and treatments for renal artery stenosis.

Atherosclerotic renal artery stenosis (ARAS) is a common and complicated disease, which can result in high blood pressure and loss of kidney function. Although progress has been made in the understanding and treatment of hypertension in relation to ARAS, much less progress has been made in the area of renal function. Here we discuss current treatment options in regard to medical therapy and revascularization.

Passive immunization against marinobufagenin attenuates renal fibrosis and improves renal function in experimental renal disease.

Background: We have shown that the cardiotonic steroid marinobufagenin (MBG) is elevated in clinical and experimental renal disease, and significantly contributes to the development of experimental uremic cardiomyopathy induced by removal of five-sixths of the kidney (5/6 nephrectomy; PNx) in the rat. We have demonstrated that both active and passive immunization against MBG with an anti-MBG monoclonal antibody (mAb 3E9) significantly attenuated cardiac fibrosis following PNx. In the present study we sought to determine whether the use of mAb 3E9 could improve renal function following PNx.

Cyclic 3', 5' guanosine monophosphate and larval midgut ecdysone 20-monooxygenase activity of the tobacco hornworm, Manduca sexta.

During the last larval stadium of the tobacco hornworm, Manduca sexta, midgut ecdysone 20-monooxygenase (E20M) activity increases 50-fold coincident with wandering onset. In our study, the effects of the ecdysone agonist RH-5849 and second messengers, dibutyryl cyclic 3', 5' adenosine monophosphate (dibutyryl cAMP) and dibutyryl cyclic 3', 5' guanosine monophosphate (dibutyryl cGMP), either alone or combined with other additives, on midgut E20M were assessed in vitro and in vivo. Pre-incubation of midguts with dibutyryl cAMP was ineffective, but dibutyryl cGMP elevated E20M activity.