Targeted stimulation of the vagus nerve reduces renal injury in female mice with systemic lupus erythematosus.

Pharmacological stimulation of the vagus nerve has been shown to suppress inflammation and reduce blood pressure in a murine model of systemic lupus erythematosus (SLE) that is characterized by hypertension, inflammation, renal injury and dysautonomia. The present study aims to directly stimulate vagal nerves at the level of the dorsal motor nucleus of the vagus (DMV) using designer receptors exclusively activated by designer drugs (DREADDs) to determine if there is similar protection and confirm mechanism. Female NZBWF1/J (SLE) mice and NZW/LacJ mice (controls, labeled as NZW throughout) received bilateral microinjections of pAAV-hSyn-hM3D(Gq)-mCherry or control virus into the DMV at 31 weeks of age.

Renal TLR-7/TNF-α pathway as a potential female-specific mechanism in the pathogenesis of autoimmune-induced hypertension.

Hypertension is prevalent in patients with systemic lupus erythematosus (SLE). The goal of the current study is to track the pathogenesis of hypertension and renal injury in SLE, identify contributory mechanisms, and highlight differences in disease development among sexes. Mean arterial pressure was measured in conscious male and female SLE () and control () mice at 34-35 wk of age using indwelling arterial catheters.

Should Renal Inflammation Be Targeted While Treating Hypertension?

Despite extensive research and a plethora of therapeutic options, hypertension continues to be a global burden. Understanding of the pathological roles of known and underexplored cellular and molecular pathways in the development and maintenance of hypertension is critical to advance the field. Immune system overactivation and inflammation in the kidneys are proposed alternative mechanisms of hypertension, and resistant hypertension.

Neogenin pathway positively regulates fibronectin production by glomerular mesangial cells.

Neogenin, a transmembrane receptor, was recently found in kidney cells and immune cells. However, the function of neogenin signaling in kidney is not clear. Mesangial cells (MCs) are a major source of extracellular matrix (ECM) proteins in glomerulus.

Enhanced Orai1-mediated store-operated Ca channel/calpain signaling contributes to high glucose-induced podocyte injury.

Podocyte injury induced by hyperglycemia is the main cause of kidney dysfunction in diabetic nephropathy. However, the underlying mechanism is unclear. Store-operated Ca entry (SOCE) regulates a diversity of cellular processes in a variety of cell types.

Store-operated calcium entry: Pivotal roles in renal physiology and pathophysiology.

Research conducted over the last two decades has dramatically advanced the understanding of store-operated calcium channels (SOCC) and their impact on renal function. Kidneys contain many types of cells, including those specialized for glomerular filtration (fenestrated capillary endothelium, podocytes), water and solute transport (tubular epithelium), and regulation of glomerular filtration and renal blood flow (vascular smooth muscle cells, mesangial cells). The highly integrated function of these myriad cells effects renal control of blood pressure, extracellular fluid volume and osmolality, electrolyte balance, and acid-base homeostasis.

Inhibition of interleukin-6 on matrix protein production by glomerular mesangial cells and the pathway involved.

Activation of immunological pathways and disturbances of extracellular matrix (ECM) dynamics are important contributors to the pathogenesis of chronic kidney diseases. Glomerular mesangial cells (MCs) are critical for homeostasis of glomerular ECM dynamics. Interleukin-6 (IL-6) can act as a pro/anti-inflammatory agent relative to cell types and conditions.

Inhibitor of myogenic differentiation family isoform a, a new positive regulator of fibronectin production by glomerular mesangial cells.

Overproduction of extracellular matrix proteins, including fibronectin by mesangial cells (MCs), contributes to diabetic nephropathy. Inhibitor of myogenic differentiation family isoform a (I-mfa) is a multifunctional cytosolic protein functioning as a transcriptional modulator or plasma channel protein regulator. However, its renal effects are unknown.

Glucagon-like peptide-1 receptor pathway inhibits extracellular matrix production by mesangial cells through store-operated Ca channel.

Unlabelled: Glomerular mesangial cell is the major source of mesangial matrix. Our previous study demonstrated that store-operated Ca channel signaling suppressed extracellular matrix protein production by mesangial cells. Recent studies demonstrated that glucagon-like peptide-1 receptor (GLP-1R) pathway had renoprotective effects.

Comparison of diabetic nephropathy between male and female eNOS/ mice.

Sex is an important biological variable that impacts diverse physiological and pathological processes, including the progression of diabetic nephropathy. Diabetic nephropathy is one of the most common complications of diabetes mellitus and is the leading cause of end-stage renal disease. The endothelial nitric oxide synthase-deficient (eNOS) / mouse is an appropriate and valuable model to study mechanisms in the development of diabetic nephropathy because of the similarities of the features of diabetic kidney disease in this model to those in humans.

Mechanisms of Sex Disparities in Cardiovascular Function and Remodeling.

Epidemiological studies demonstrate disparities between men and women in cardiovascular disease prevalence, clinical symptoms, treatments, and outcomes. Enrollment of women in clinical trials is lower than men, and experimental studies investigating molecular mechanisms and efficacy of certain therapeutics in cardiovascular disease have been primarily conducted in male animals. These practices bias data interpretation and limit the implication of research findings in female clinical populations.

Short-term high-glucose treatment decreased abundance of Orai1 protein through posttranslational mechanisms in rat mesangial cells.

The short-term effect of high-glucose (HG) treatment on store-operated Ca entry in mesangial cells (MCs) is not well-known. The aim of the present study was to determine whether and how HG treatment for a short period altered protein abundance of Orai1, the channel mediating store-operated Ca entry in MCs. Rat and human MCs were exposed to HG (25 mM) for 2, 4, 8, and 24 h, and the abundance of Orai1 protein was significantly decreased at the time points of 8 and 16 h.

Increased glomerular filtration rate and impaired contractile function of mesangial cells in TRPC6 knockout mice.

The present study was conducted to determine if TRPC6 regulates glomerular filtration rate (GFR) and the contractile function of glomerular mesangial cells (MCs). GFR was assessed in conscious TRPC6 wild type and knockout mice, and in anesthetized rats with and without in vivo knockdown of TRPC6 in kidneys. We found that GFR was significantly greater, and serum creatinine level was significantly lower in TRPC6 deficient mice.

Store-operated calcium entry suppressed the TGF-β1/Smad3 signaling pathway in glomerular mesangial cells.

Our previous study demonstrated that the abundance of extracellular matrix proteins was suppressed by store-operated Ca entry (SOCE) in mesangial cells (MCs). The present study was conducted to investigate the underlying mechanism focused on the transforming growth factor-β1 (TGF-β1)/Smad3 pathway, a critical pathway for ECM expansion in diabetic kidneys. We hypothesized that SOCE suppressed ECM protein expression by inhibiting this pathway in MCs.

Negative regulation of Smad1 pathway and collagen IV expression by store-operated Ca entry in glomerular mesangial cells.

Collagen IV (Col IV) is a major component of expanded glomerular extracellular matrix in diabetic nephropathy and Smad1 is a key molecule regulating Col IV expression in mesangial cells (MCs). The present study was conducted to determine if Smad1 pathway and Col IV protein abundance were regulated by store-operated Ca entry (SOCE). In cultured human MCs, pharmacological inhibition of SOCE significantly increased the total amount of Smad1 protein.

Canonical Transient Receptor Potential 6 Channel: A New Target of Reactive Oxygen Species in Renal Physiology and Pathology.

Significance: Regulation of Ca signaling cascade by reactive oxygen species (ROS) is becoming increasingly evident and this regulation represents a key mechanism for control of many fundamental cellular functions. Canonical transient receptor potential (TRPC) 6, a member of Ca-conductive channel in the TRPC family, is widely expressed in kidney cells, including glomerular mesangial cells, podocytes, tubular epithelial cells, and vascular myocytes in renal microvasculature. Both overproduction of ROS and dysfunction of TRPC6 channel are involved in renal injury in animal models and human subjects.

Store-operated calcium entry and diabetic complications.

Store-operated Ca(2+) entry (SOCE) is mediated by the store-operated Ca(2+) channel (SOC) that opens upon depletion of internal Ca(2+) stores following activation of G protein-coupled receptors or receptor tyrosine kinases. Over the past two decades, the physiological and pathological relevance of SOCE has been extensively studied. Recently, accumulating evidence suggests associations of altered SOCE with diabetic complications.

Store-Operated Ca2+ Channels in Mesangial Cells Inhibit Matrix Protein Expression.

Accumulation of extracellular matrix derived from glomerular mesangial cells is an early feature of diabetic nephropathy. Ca(2+) signals mediated by store-operated Ca(2+) channels regulate protein production in a variety of cell types. The aim of this study was to determine the effect of store-operated Ca(2+) channels in mesangial cells on extracellular matrix protein expression.

Impairment of hepatic nuclear factor-4α binding to the Stim1 promoter contributes to high glucose-induced upregulation of STIM1 expression in glomerular mesangial cells.

The present study was carried out to investigate if hepatic nuclear factor (HNF)4α contributed to the high glucose-induced increase in stromal interacting molecule (STIM)1 protein abundance in glomerular mesangial cells (MCs). Western blot and immunofluorescence experiments showed HNF4α expression in MCs. Knockdown of HNF4α using a small interfering RNA approach significantly increased mRNA expression levels of both STIM1 and Orai1 and protein expression levels of STIM1 in cultured human MCs.

P7170: A Novel Molecule with Unique Profile of mTORC1/C2 and Activin Receptor-like Kinase 1 Inhibition Leading to Antitumor and Antiangiogenic Activity.

The mTOR pathway is often upregulated in cancer and thus intensively pursued as a target to design novel anticancer therapies. Approved and emerging drugs targeting the mTOR pathway have positively affected the clinical landscape. Recently, activin receptor-like kinase 1 (ALK1), belonging to the TGFβ receptor family, has been reported as an emerging target for antiangiogenic cancer therapy.

High glucose and diabetes enhanced store-operated Ca(2+) entry and increased expression of its signaling proteins in mesangial cells.

The present study was conducted to determine whether and how store-operated Ca(2+) entry (SOCE) in glomerular mesangial cells (MCs) was altered by high glucose (HG) and diabetes. Human MCs were treated with either normal glucose or HG for different time periods. Cyclopiazonic acid-induced SOCE was significantly greater in the MCs with 7-day HG treatment and the response was completely abolished by GSK-7975A, a selective inhibitor of store-operated Ca(2+) channels.

Impact of long term Yoga practice on sleep quality and quality of life in the elderly.

Background: Sleep disturbances and decline in the physical functionality are common conditions associated with aging. Pharmacological treatment of sleep disturbances can be associated with various adverse effects. Short term trials of Yoga on sleep have shown beneficial effects.

Nuclear factor κB mediates suppression of canonical transient receptor potential 6 expression by reactive oxygen species and protein kinase C in kidney cells.

This study was carried out to explore the molecular mechanism for down-regulation of TRPC6 expression in the reactive oxygen species (ROS)/PKC signaling in kidney cells. In cultured human mesangial cells, H2O2 and TNF-α inhibited TRPC6 mRNA expression in a time-dependent manner. Inhibition of NF-κB reversed both H2O2- and phorbol 12-myristate 13-acetate (PMA)-induced decrease in TRPC6 protein expression.