Sodium-glucose cotransporter 2 inhibition does not improve the acute pressure natriuresis response in rats with type 1 diabetes.

New Findings: What is the central question of this study? Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce cardiovascular risk in patients with both diabetic and non-diabetic kidney disease: can SGLT2 inhibition improve renal pressure natriuresis (PN), an important mechanism for long-term blood pressure control, which is impaired in type 1 diabetes mellitus (T1DM)? What is the main finding and its importance? The SGLT2 inhibitor dapagliflozin did not enhance the acute in vivo PN response in either healthy or T1DM Sprague-Dawley rats. The data suggest that the mechanism underpinning the clinical benefits of SGLT2 inhibitors on health is unlikely to be due to an enhanced natriuretic response to increased blood pressure.

Abstract: Type 1 diabetes mellitus (T1DM) leads to serious complications including premature cardiovascular and kidney disease.

Physiological regulation of phosphate homeostasis.

Phosphate homeostasis is dependent on the interaction and coordination of four main organ systems: thyroid/parathyroids, gastrointestinal tract, bone and kidneys, and three key hormonal regulators, 1,25-hydroxyvitamin D3, parathyroid hormone and FGF23 with its co- factor klotho. Phosphorus is a critical nutritional element for normal cellular function, but in excess can be toxic to tissues, particularly the vasculature. As phosphate, it also has an important interaction and inter-dependence with calcium and calcium homeostasis sharing some of the same controlling hormones, although this is not covered in our article.

The Complexities of Organ Crosstalk in Phosphate Homeostasis: Time to Put Phosphate Sensing Back in the Limelight.

Phosphate homeostasis is essential for health and is achieved via interaction between the bone, kidney, small intestine, and parathyroid glands and via intricate processes involving phosphate transporters, phosphate sensors, and circulating hormones. Numerous genetic and acquired disorders are associated with disruption in these processes and can lead to significant morbidity and mortality. The role of the kidney in phosphate homeostasis is well known, although it is recognized that the cellular mechanisms in murine models and humans are different.

Diet-induced iron deficiency in rats impacts small intestinal calcium and phosphate absorption.

Aims: Recent reports suggest that iron deficiency impacts both intestinal calcium and phosphate absorption, although the exact transport pathways and intestinal segment responsible have not been determined. Therefore, we aimed to systematically investigate the impact of iron deficiency on the cellular mechanisms of transcellular and paracellular calcium and phosphate transport in different regions of the rat small intestine.

Methods: Adult, male Sprague-Dawley rats were maintained on a control or iron-deficient diet for 2 weeks and changes in intestinal calcium and phosphate uptake were determined using the in situ intestinal loop technique.

Virtual clinics for glaucoma care - Patients' and clinicians' experiences and perceptions: a qualitative evaluation.

Background: The role of glaucoma virtual clinics has developed to help meet demand for capacity within busy glaucoma services. There is limited research of patient and clinician experiences and perceptions of these clinics and the aim of this study is to provide further information to help improve patient experience and guide service delivery.

Methods: A mixed methods research design was employed comprising of a patient satisfaction survey, and patient and clinician interviews.

1,25(OH) vitamin D stimulates active phosphate transport but not paracellular phosphate absorption in mouse intestine.

Key Points: Intestinal absorption of phosphate proceeds via an active/transcellular route mostly mediated by NaPi-IIb/Slc34a2 and a poorly characterized passive/paracellular pathway. Intestinal phosphate absorption and expression of NaPi-IIb are stimulated by 1,25(OH) vitamin D but whether NaPi-IIb is the only target under hormonal control remains unknown. We report that administration of 1,25(OH) vitamin D to wild-type mice resulted in the expected increase in active transport of phosphate in jejunum, without changing paracellular fluxes.

Artificial Sweeteners Disrupt Tight Junctions and Barrier Function in the Intestinal Epithelium through Activation of the Sweet Taste Receptor, T1R3.

The breakdown of the intestinal epithelial barrier and subsequent increase in intestinal permeability can lead to systemic inflammatory diseases and multiple-organ failure. Nutrition impacts the intestinal barrier, with dietary components such as gluten increasing permeability. Artificial sweeteners are increasingly consumed by the general public in a range of foods and drinks.

The absorbing life of bile acids.

Hyperphosphatemia increases cardiovascular complications and all-cause mortality rate in patients with chronic kidney disease. Targeting the processes involved in dietary phosphate absorption is an attractive means for reducing this phosphate burden. We do not, however, fully understand this process and how it is regulated.

The role of SLC34A2 in intestinal phosphate absorption and phosphate homeostasis.

There has recently been significant interest in the concept of directly targeting intestinal phosphate transport to control hyperphosphatemia in patients with chronic kidney disease. However, we do not have a complete understanding of the cellular mechanisms that govern dietary phosphate absorption. Studies in the 1970s documented both active and passive pathways for intestinal phosphate absorption.

Clinical effectiveness of the Manchester Glaucoma Enhanced Referral Scheme.

Background: Glaucoma referral filtering schemes have operated in the UK for many years. However, there is a paucity of data on the false-negative (FN) rate. This study evaluated the clinical effectiveness of the Manchester Glaucoma Enhanced Referral Scheme (GERS), estimating both the false-positive (FP) and FN rates.

Inhibition of sodium/hydrogen exchanger 3 in the gastrointestinal tract by tenapanor reduces paracellular phosphate permeability.

Hyperphosphatemia is common in patients with chronic kidney disease and is increasingly associated with poor clinical outcomes. Current management of hyperphosphatemia with dietary restriction and oral phosphate binders often proves inadequate. Tenapanor, a minimally absorbed, small-molecule inhibitor of the sodium/hydrogen exchanger isoform 3 (NHE3), acts locally in the gastrointestinal tract to inhibit sodium absorption.

Acute saccharin infusion has no effect on renal glucose handling in normal rats in vivo.

Artificial sweeteners are extensively used by the food industry to replace sugar in food and beverages and are widely considered to be a healthy alternative. However, recent data suggest that artificial sweeteners may impact intestinal glucose absorption and that they might lead to glucose intolerance. Moreover, chronic consumption of artificial sweeteners has also been linked to detrimental changes in renal function.

Acceptability and use of glaucoma virtual clinics in the UK: a national survey of clinical leads.

Objective: The purpose of this paper is to describe the findings of a national survey that aimed to estimate the proportion of Hospital Eye Service (HES) units using glaucoma virtual clinics, to determine how these services differ and to gauge clinicians' views and opinions on the safety and acceptability of this model of care compared with usual care.

Methods And Analysis: This 12-question survey was disseminated nationally to 92 clinical lead consultant ophthalmologists using SurveyMonkey.

Results: The response rate was 45.

Postprandial adjustments in renal phosphate excretion do not involve a gut-derived phosphaturic factor.

What is the central question of this study? Does a previously hypothesized signalling mechanism, believed to detect postprandial increases in intestinal phosphate and that can stimulate the kidneys to rapidly excrete phosphate, operate under physiological conditions? What is the main finding and its importance? Contrary to earlier reports, rapid signalling between the small intestine and kidney mediated by a gut-derived phosphaturic factor in response to a physiological intestinal phosphate load is not supported by the present findings; moreover, hyperphosphataemia and increased parathyroid hormone concentrations are likely to be the underlying factors responsible for the phosphaturia following a supraphysiological intestinal phosphate load. To date, the role of the small intestine in the regulation of postprandial phosphate homeostasis has remained unclear and controversial. Previous studies have proposed the presence of a gut-derived phosphaturic factor that acts independently of changes in plasma phosphate concentration or parathyroid hormone (PTH) concentration; however, these early studies used duodenal luminal phosphate concentrations in the molar range, and therefore, the physiological relevance of this is uncertain.

Putative tissue location and function of the SLC5 family member SGLT3.

What is the topic of this review? This review summarizes the evidence on the localization, electrophysiological properties, agonist specificity and putative physiological role of sodium-glucose transporter 3 (SGLT3). What advances does it highlight? Published information is reviewed in some detail by comparing human and rodent isoforms, as well as advances in testing hypotheses for the physiological role of SGLT3 as a glucose sensor or incretin release mediator. We provide a critical overview of available published data and discuss a putative functional role for SGLT3 in human and mouse physiology.

Experimental type II diabetes and related models of impaired glucose metabolism differentially regulate glucose transporters at the proximal tubule brush border membrane.

What is the central question of this study? Although SGLT2 inhibitors represent a promising treatment for patients suffering from diabetic nephropathy, the influence of metabolic disruption on the expression and function of glucose transporters is largely unknown. What is the main finding and its importance? In vivo models of metabolic disruption (Goto-Kakizaki type II diabetic rat and junk-food diet) demonstrate increased expression of SGLT1, SGLT2 and GLUT2 in the proximal tubule brush border. In the type II diabetic model, this is accompanied by increased SGLT- and GLUT-mediated glucose uptake.

Experimental and regional variations in Na+-dependent and Na+-independent phosphate transport along the rat small intestine and colon.

Despite the importance of extracellular phosphate in many essential biological processes, the mechanisms of phosphate transport across the epithelium of different intestinal segments remain unclear. We have used an in vitro method to investigate phosphate transport at the brush border membrane (BBM) of intact intestinal segments and an in vivo method to study transepithelial phosphate absorption. We have used micromolar phosphate concentrations known to favor NaPi-IIb-mediated transport, and millimolar concentrations that are representative of the levels we have measured in luminal contents, to compare the extent of Na(+)-dependent and Na(+)-independent phosphate transport along the rat duodenum, jejunum, ileum, and proximal and distal colon.

Intestinal phosphate transport: a therapeutic target in chronic kidney disease and beyond?

Hyperphosphatemia is a serious complication of late-stage chronic kidney disease (CKD), contributing to the increased cardiovascular morbidity and mortality seen in this patient group. Results from retrospective studies suggest that small increases in serum phosphate concentration, within the normal or near-normal range, also correlate with increased cardiovascular morbidity and mortality and have led to the suggestion that detection and preventative treatment of positive phosphate balance is important in healthy individuals as well as in those with CKD. Phosphate homeostasis is maintained by the crosstalk between intestinal phosphate absorption and renal phosphate excretion; however, relatively little is known about the mechanisms of intestinal phosphate transport.

The role of the gastrointestinal tract in phosphate homeostasis in health and chronic kidney disease.

Purpose Of Review: For a number of years, there has been increasing interest in the concept of directly targeting intestinal phosphate transport to control hyperphosphatemia in chronic kidney disease. However, progress has been slow due to the paucity of information on the mechanisms involved in intestinal phosphate absorption. This editorial highlights the most recent developments in our understanding of this process and the role of the intestine in the maintenance of phosphate balance.

Erythropoietin regulates intestinal iron absorption in a rat model of chronic renal failure.

Erythropoietin is produced by the kidney and stimulates erythropoiesis; however, in chronic renal disease its levels are reduced and patients develop anemia that is treatable with iron and recombinant hormone. The mechanism by which erythropoietin improves iron homeostasis is still unclear, but it may involve suppression of the iron regulatory peptide hepcidin and/or a direct effect on intestinal iron absorption. To investigate these possibilities, we used the well-established 5/6th nephrectomy rat model of chronic renal failure with or without human recombinant erythropoietin treatment.

Phosphate homeostasis and the renal-gastrointestinal axis.

Transport of phosphate across intestinal and renal epithelia is essential for normal phosphate balance, yet we know less about the mechanisms and regulation of intestinal phosphate absorption than we do about phosphate handling by the kidney. Recent studies have provided strong evidence that the sodium-phosphate cotransporter NaPi-IIb is responsible for sodium-dependent phosphate absorption by the small intestine, and it might be that this protein can link changes in dietary phosphate to altered renal phosphate excretion to maintain phosphate balance. Evidence is also emerging that specific regions of the small intestine adapt differently to acute or chronic changes in dietary phosphate load and that phosphatonins inhibit both renal and intestinal phosphate transport.

Hepcidin decreases iron transporter expression in vivo in mouse duodenum and spleen and in vitro in THP-1 macrophages and intestinal Caco-2 cells.

Hepcidin is thought to control iron metabolism by interacting with the iron efflux transporter ferroportin. In macrophages, there is compelling evidence that hepcidin directly regulates ferroportin protein expression. However, the effects of hepcidin on intestinal ferroportin levels are less conclusive.

Matrix extracellular phosphoglycoprotein inhibits phosphate transport.

The role of putative humoral factors, known as phosphatonins, in phosphate homeostasis and the relationship between phosphate handling by the kidney and gastrointestinal tract are incompletely understood. Matrix extracellular phosphoglycoprotein (MEPE), one of several candidate phosphatonins, promotes phosphaturia, but whether it also affects intestinal phosphate absorption is unknown. Here, using the in situ intestinal loop technique, we demonstrated that short-term infusion of MEPE inhibits phosphate absorption in the jejunum but not the duodenum.

Sodium-dependent regulation of renal amiloride-sensitive currents by apical P2 receptors.

The epithelial sodium channel (ENaC) plays a major role in the regulation of sodium balance and BP by controlling Na(+) reabsorption along the renal distal tubule and collecting duct (CD). ENaC activity is affected by extracellular nucleotides acting on P2 receptors (P2R); however, there remain uncertainties over the P2R subtype(s) involved, the molecular mechanism(s) responsible, and their physiologic role. This study investigated the relationship between apical P2R and ENaC activity by assessing the effects of P2R agonists on amiloride-sensitive current in the rat CD.