Compared with males, females have lower BP before age 60, blunted hypertensive response to angiotensin II, and a leftward shift in pressure natriuresis. This study tested the concept that this female advantage associates distinct sexual dimorphic pattern of transporters along nephron. We applied quantitative immunoblotting generate profiles transporters, channels, claudins, selected regulators both sexes assessed physiologic consequences differences. In rats, excreted saline load more...

Glucagon-like peptide-1 (GLP-1) is a gut incretin hormone considered promising therapeutic agent for type 2 diabetes because it stimulates beta cell proliferation and insulin secretion in glucose-dependent manner. Cumulative evidence supports role GLP-1 modulating renal function; however, the mechanisms by which induces diuresis natriuresis have not been completely established. This study aimed to define cellular molecular mediating effects of GLP-1. (1 μg·kg(-1)·min(-1)) was intravenously...

Na(+)-glucose cotransporter 1 (SGLT1)-mediated glucose uptake leads to activation of Na(+)-H(+) exchanger 3 (NHE3) in the intestine by a process that is not dependent on metabolism. This coactivation may be important for postprandial nutrient uptake. However, it remains determined whether SGLT-mediated regulates NHE3-mediated NaHCO3 reabsorption renal proximal tubule. Considering this nephron segment also expresses SGLT2 and kidneys show significant variations daily availability, goal study...

The gut incretin hormone glucagon-like peptide 1 (GLP-1) is released in response to ingested nutrients and enhances insulin secretion. In addition its insulinotropic properties, GLP-1 has been shown have natriuretic actions paralleled by a diminished proton We therefore studied the role of receptor agonist exendin-4 modulating activity Na(+)/H(+) exchanger NHE3 LLC-PK(1) cells. found that NHE3-mediated Na(+)-dependent intracellular pH (pH(i)) recovery decreased approximately 50% after 30-min...

Background— The present study addresses the hypothesis that activity of dipeptidyl peptidase IV (DPPIV), an enzyme inactivates peptides possess cardioprotective actions, correlates with adverse outcomes in heart failure (HF). therapeutic potential DPPIV inhibition preventing cardiac dysfunction is also investigated. Methods and Results— Measurements blood samples obtained from 190 patients HF 42 controls demonstrated exhibited increase ≈130% circulating compared healthy subjects....

The present study aimed to assess the effect of specific dipeptidyl peptidase IV (DPPIV) inhibitor sitagliptin on blood pressure and renal function in young prehypertensive (5-week-old) adult spontaneously hypertensive rats (SHRs; 14-week-old).Sitagliptin (40 mg/kg twice daily) was given by oral gavage (Y-SHR + IDPPIV) (A-SHR SHRs for 8 days. Kidney assessed daily compared with age-matched vehicle-treated SHR A-SHR) normotensive Wistar-Kyoto (Y-WKY A-WKY). Arterial measured these animals at...

Glucagon like peptide-1 (GLP-1) is an incretin hormone constantly secreted from the intestine at low basal levels in fasted state; plasma concentrations rise rapidly after nutrient ingestion. Upon release, GLP-1 exerts insulinotropic effects via a G protein-coupled receptor, stimulation of adenylyl cyclase, and cAMP generation. Although primarily involved glucose homeostasis, can induce diuresis natriuresis when administered pharmacological doses humans rodents. However, whether endogenous...

SGLT2 inhibitors reduce the risk of heart failure (HF) mortality and morbidity, regardless presence or absence diabetes, but mechanisms underlying this benefit remain unclear. Experiments with nondiabetic HF rats tested hypothesis that inhibitor empagliflozin (EMPA) inhibits proximal tubule (PT) NHE3 activity improves renal salt water handling.Male Wistar were subjected to myocardial infarction sham operation. After 4 weeks, developed treated EMPA untreated for an additional weeks....

In an attempt to identify proteins that assemble with the apical membrane Na+-H+ exchanger isoform NHE3, we generated monoclonal antibodies (mAbs) against affinity-purified NHE3 protein complexes isolated from solubilized renal microvillus vesicles. Hybridomas were selected based on their ability immunoprecipitate NHE3. We have characterized in detail one of mAbs (1D11) specifically co-precipitated but not villin or NaPi-2. Western blot analyses membranes and immunoelectron microscopy kidney...

Transfection studies using mutant constructs have implicated one or both protein kinase A (PKA) consensus phosphorylation sites [serines 552 and 605 in rat Na(+)/H(+) exchanger type 3 (NHE3)] as critical for mediating inhibition of NHE3 response to several stimuli including dopamine. However, whether these is actually phosphorylated endogenous proximal tubule cells unknown. The purpose this study was generate phosphospecific antibodies so that the state serine residues could be assessed...

We recently reported that NHE3 exists in multimeric complexes with dipeptidyl peptidase IV (DPPIV) renal brush-border membranes. To examine the possible role of DPPIV modulating activity, we evaluated whether specific competitive inhibitors bind to active site affect activity OKP line opossum kidney proximal tubule cells. The diprotin A and P32/98 significantly reduced whereas inactive isomer P34/98 had no effect. did not reduce another transport process, Na-phosphate cotransport. Effects on...

In the microvillar microdomain of kidney brush border, sodium hydrogen exchanger type 3 (NHE3) exists in physical complexes with serine protease dipeptidyl peptidase IV (DPPIV). The purpose this study was to explore functional relationship between NHE3 and DPPIV intact proximal tubule vivo. To end, male Wistar rats were treated an injection reversible inhibitor Lys [Z(NO2)]-pyrrolidide (I40; 60 mg.kg(-1).day(-1) ip) for 7 days. Rats injected equal amounts noninhibitory compound...

The purpose of the current study was to test hypothesis that dipeptidyl peptidase IV (DPPIV) inhibitor sitagliptin, which exerts anti-hyperglycemic and anti-hypertensive effects, upregulates GLUT4 translocation, protein levels, and/or mRNA expression in heart skeletal muscle spontaneously hypertensive rats (SHRs). Ten days treatment with sitagliptin (40 mg/kg twice daily) decreased plasma DPPIV activity both young (Y, 5-week-old) adult (A, 20-week-old) SHRs similar extents (~85%). However,...

Renal nerve stimulation at a low frequency (below 2 Hz) causes water and sodium reabsorption via α 1 -adrenoreceptor tubular activation, process independent of changes in systemic blood pressure, renal flow, or glomerular filtration rate. However, the underlying mechanism is not fully understood. Since sympathetic nervous system intrarenal ANG II appear to act synergistically mediate reabsorption, we hypothesized that low-frequency acute electrical (ESRN) activates NHE3-mediated AT receptor...

The pharmacological administration of GLP-1R (glucagon-like peptide-1 receptor) agonists reduces blood pressure (BP) in type 2 diabetes mellitus and nondiabetic patients. This study tested the hypothesis that endogenous signaling influences regulation BP. To this end, SHRs (spontaneously hypertensive rats) Wistar rats were treated with antagonist Ex9 (exendin-9) or vehicle for 4 weeks. Rats receiving agonist Ex4 (exenatide) used as an additional control. We found blockade baseline by...

Sodium-glucose cotransporter 2 (SGLT2) inhibitors, also known as gliflozins, improve glycemia by suppressing glucose reuptake in the renal proximal tubule. Currently, SGLT2 inhibitors are primarily indicated antidiabetic agents; however, their benefits extend far beyond control. Cardiovascular outcome trials that all studied remarkably and consistently reduce cardiovascular mortality hospitalization for heart failure (HF) type diabetes (T2D) patients. Nevertheless, mechanisms underlying...

This study suggests that reduced NHE3-mediated sodium reabsorption in the renal proximal tubule may account, at least part, for BP-lowering effect of SGLT2 inhibitors setting hypertension. It also demonstrates chronic treatment with upregulates NCC activity, phosphorylation, and expression distal normotensive but not hypertensive rats. inhibitor-mediated upregulation seems crucial to counteract natriuresis subjects normal BP.

Dysregulated renin-angiotensin system (RAS) signaling contributes to elevated blood pressure (BP), inflammation, and organ damage in systemic arterial hypertension (HTN). We have demonstrated that hypertensive humans rats exhibit higher expression of classic RAS components lower counterregulatory the lungs compared with normotensive counterparts. Here, we investigated whether BP control could restore balance between [angiotensin I-converting enzyme 2 (ACE)/angiotensin II (Ang II)] (ACE2)/Ang...

Background: Cisplatin, a chemotherapeutic agent, induces kidney magnesium wasting and hypomagnesemia. Recent studies suggest that SGLT2 inhibitors elevate serum concentration in patients with or without diabetes. We hypothesized the inhibitor empagliflozin attenuates acute cisplatin-induced hypomagnesemia by acting on thick ascending limb (TAL) distal convoluted tubule (DCT), key sites of reabsorption. Methods: Adult male Wistar rats received weekly treatments cisplatin (2.5 mg/kg) saline...

Heart failure (HF) is associated with a reduced effective circulating volume that drives sodium and water retention extracellular expansion. We therefore hypothesized Na + /H exchanger isoform 3 (NHE3), the major apical transcellular pathway for reabsorption in proximal tubule, upregulated an experimental model of HF. HF was induced male rats by left ventricle radiofrequency ablation. Sham-operated (sham) were used as controls. At 6 wk after surgery, exhibited cardiac dysfunction dramatic...

Abnormalities in renal proximal tubular (PT) sodium transport play an important role the pathophysiology of essential hypertension. The Na(+)/H(+) exchanger isoform 3 (NHE3) represents major route for entry across apical membrane PT cells. We therefore aimed to assess vivo NHE3 activity and define molecular mechanisms underlying regulation before after development hypertension spontaneously hypertensive rat (SHR). function was measured as rate bicarbonate reabsorption by means stationary...

Abstract The antidiabetic agent class of sodium-glucose cotransporter 2 (SGLT2) inhibitors confer unprecedented cardiovascular benefits beyond glycemic control, including reducing the risk fatal ventricular arrhythmias. However, impact SGLT2 on electrophysiological properties cardiomyocytes exposed to stimuli other than hyperglycemia remains elusive. This investigation tested hypothesis that inhibitor empagliflozin (EMPA) affects cardiomyocyte electrical activity under hypoxic conditions....