Genetic deletion of the kidney sodium/proton exchanger-3 (NHE3) does not alter calcium and phosphate balance due to compensatory responses.

The sodium/proton exchanger-3 (NHE3) plays a major role in acid-base and extracellular volume regulation and is also implicated in calcium homeostasis. As calcium and phosphate balances are closely linked, we hypothesized that there was a functional link between kidney NHE3 activity, calcium, and phosphate balance. Therefore, we examined calcium and phosphate homeostasis in kidney tubule-specific NHE3 knockout mice (NHE3 mice).

Vitamin D suppresses Npt2c abundance and differentially modulates phosphate and calcium homeostasis in Npt2a knockout mice.

Vitamin D is clinically used for the treatment of vitamin D deficiency or osteoporosis, partially because of its role in regulating phosphate (P) and calcium (Ca) homeostasis. The renal sodium-phosphate cotransporter 2a (Npt2a) plays an important role in P homeostasis; however, the role of vitamin D in hypophosphatemia has never been investigated. We administered vehicle or vitamin D to wild-type (WT) mice or hypophosphatemic Npt2a mice.

Intravenous ferric carboxymaltose and ferric derisomaltose alter the intestinal microbiome in female iron-deficient anemic mice.

Iron deficiency anemia (IDA) is a leading global health concern affecting approximately 30% of the population. Treatment for IDA consists of replenishment of iron stores, either by oral or intravenous (IV) supplementation. There is a complex bidirectional interplay between the gut microbiota, the host's iron status, and dietary iron availability.

Knowledge, attitude, and practice of ophthalmic manifestations in COVID-19 patients at a tertiary care center.

Purpose: Since the start of the COVID-19 pandemic, various manifestations have been reported, including ophthalmic symptoms, especially with the different mutations and variants that have occurred over the last few years. In view of this, our study was conducted to gauge the knowledge, attitude, and practices of patients toward the ophthalmic manifestations of COVID-19.

Methods: This was a hospital-based, cross-sectional, observational study.

Sodium phosphate cotransporter 2a inhibitors: potential therapeutic uses.

Purpose Of Review: Targeting sodium phosphate cotransporter 2a (Npt2a) offers a novel strategy for treating hyperphosphatemia in chronic kidney disease (CKD). Here we review recent studies on the efficacy of Npt2a inhibition, its plasma phosphate (Pi)-lowering effects, as well as potential "off-target" beneficial effects on cardiovascular consequences.

Recent Findings: Two novel Npt2a-selective inhibitors (PF-06869206 and BAY-767) have been developed.

Intestine-Specific NHE3 Deletion in Adulthood Causes Microbial Dysbiosis.

In the intestine, the Na/H exchanger 3 (NHE3) plays a critical role for Na and fluid absorption. NHE3 deficiency predisposes patients to inflammatory bowel disease (IBD). In mice, selective deletion of intestinal NHE3 causes various local and systemic pathologies due to dramatic changes in the intestinal environment, which can influence microbiota colonization.

NHE3 in the thick ascending limb is required for sustained but not acute furosemide-induced urinary acidification.

Na/H exchanger isoform 3 (NHE3) facilitates Na reabsorption and H secretion by the kidneys. Despite stronger NHE3 abundance in the thick ascending limb (TAL) compared with the S1 and S2 segments of the proximal tubule, the role of NHE3 in the TAL is poorly understood. To investigate the role of NHE3 in the TAL, we generated and phenotyped TAL-specific NHE3 knockout (NHE3) mice.

Npt2a as a target for treating hyperphosphatemia.

Hyperphosphatemia results from an imbalance in phosphate (Pi) homeostasis. In patients with and without reduced kidney function, hyperphosphatemia is associated with cardiovascular complications. The current mainstays in the management of hyperphosphatemia are oral Pi binder and dietary Pi restriction.

Enhanced phosphate absorption in intestinal epithelial cell-specific NHE3 knockout mice.

Aims: The kidneys play a major role in maintaining P homeostasis. Patients in later stages of CKD develop hyperphosphatemia. One novel treatment option is tenapanor, an intestinal-specific NHE3 inhibitor.

Genetic deletion of connexin 37 causes polyuria and polydipsia.

The connexin 37 (Cx37) channel is clustered at gap junctions between cells in the renal vasculature or the renal tubule where it is abundant in basolateral cell interdigitations and infoldings of epithelial cells in the proximal tubule, thick ascending limb, distal convoluted tubule and collecting duct; however, physiological data regarding its role are limited. In this study, we investigated the role of Cx37 in fluid homeostasis using mice with a global deletion of Cx37 (Cx37-/- mice). Under baseline conditions, Cx37-/- had ~40% higher fluid intake associated with ~40% lower urine osmolality compared to wild-type (WT) mice.

PF-06869206 is a selective inhibitor of renal P transport: evidence from in vitro and in vivo studies.

Plasma phosphate (P) levels are tightly controlled, and elevated plasma P levels are associated with an increased risk of cardiovascular complications and death. Two renal transport proteins mediate the majority of P reabsorption: Na-phosphate cotransporters Npt2a and Npt2c, with Npt2a accounting for 70-80% of P reabsorption. The aim of the present study was to determine the in vitro effects of a novel Npt2a inhibitor (PF-06869206) in opossum kidney (OK) cells as well as determine its selectivity in vivo in Npt2a knockout (Npt2a) mice.

An inducible intestinal epithelial cell-specific NHE3 knockout mouse model mimicking congenital sodium diarrhea.

The sodium-hydrogen exchanger isoform 3 (NHE3, SLC9A3) is abundantly expressed in the gastrointestinal tract and is proposed to play essential roles in Na+ and fluid absorption as well as acid-base homeostasis. Mutations in the SLC9A3 gene can cause congenital sodium diarrhea (CSD). However, understanding the precise role of intestinal NHE3 has been severely hampered due to the lack of a suitable animal model.

Pharmacological Npt2a Inhibition Causes Phosphaturia and Reduces Plasma Phosphate in Mice with Normal and Reduced Kidney Function.

Background: The kidneys play an important role in phosphate homeostasis. Patients with CKD develop hyperphosphatemia in the later stages of the disease. Currently, treatment options are limited to dietary phosphate restriction and oral phosphate binders.

Intestinal Response to Acute Intragastric and Intravenous Administration of Phosphate in Rats.

Background/aims: Phosphate (Pi) homeostasis is controlled by the intestine and kidneys whose capacities to transport Pi are under endocrine control. Several studies point to intestinal absorption as a therapeutic target to modulate Pi homeostasis. The small intestine is responsible for almost all Pi absorption in the gut, a process involving Na-dependent and independent mechanisms.

Contribution of NHE3 and dietary phosphate to lithium pharmacokinetics.

Lithium is one of the mainstays for the treatment of bipolar disorder despite its side effects on the endocrine, neurological, and renal systems. Experimentally, lithium has been used as a measure to determine proximal tubule reabsorption based on the assumption that lithium and sodium transport go in parallel in the proximal tubule. However, the exact mechanism by which lithium is reabsorbed remains elusive.

Implication of vascular endothelial growth factor A and C in revealing diagnostic lymphangiogenic markers in node-positive bladder cancer.

Several lymphangiogenic factors, such as vascular endothelial growth factors (VEGFs), have been found to drive the development of lymphatic metastasis in bladder cancer (BCa).Here, we have analyzed the gene expression of lymphangiogenic factors in tissue specimens from 12 non-muscle invasive bladder cancers (NMIBC) and 11 muscle invasive bladder cancers (MIBC), considering tumor and tumor-adjacent normal bladder areas obtained from the same organs. We then compared the results observed in patients with those obtained after treating human primary bladder microvascular endothelial cells (MEC) with either direct stimulation with VEGF-A or VEGF-C or by co-culturing (trans-well assay) MEC with bladder cancer cell lines varying in VEGF-A and VEGF-C production based on tumor grade.

Acute Adaption to Oral or Intravenous Phosphate Requires Parathyroid Hormone.

Phosphate (Pi) homeostasis is regulated by renal, intestinal, and endocrine mechanisms through which Pi intake stimulates parathyroid hormone (PTH) and fibroblast growth factor-23 secretion, increasing phosphaturia. Mechanisms underlying the early adaptive phase and the role of the intestine, however, remain ill defined. We investigated mineral, endocrine, and renal responses during the first 4 hours after intravenous and intragastric Pi loading in rats.

Adaptation of Opossum Kidney Cells to Luminal Phosphate: Effects of Phosphonoformic Acid and Kinase Inhibitors.

Background/aims: Renal reabsorption of inorganic phosphate (Pi) is mediated by SLC34 and SLC20 Na+/Pi-cotransporters the abundance of which is under hormonal control. Extracellular Pi itself also regulates the expression of cotransporters and the concentration of Pi-regulating hormones, though the signaling pathways are largely unknown. Here, we explored the mechanisms that allow renal proximal cells to adapt to changes in the concentration of Pi.

Intestinal Depletion of NaPi-IIb/Slc34a2 in Mice: Renal and Hormonal Adaptation.

The Na(+) -dependent phosphate-cotransporter NaPi-IIb (SLC34A2) is widely expressed, with intestine, lung, and testis among the organs with highest levels of mRNA abundance. In mice, the intestinal expression of NaPi-IIb is restricted to the ileum, where the cotransporter localizes specifically at the brush border membrane (BBM) and mediates the active transport of inorganic phosphate (Pi). Constitutive full ablation of NaPi-IIb is embryonically lethal whereas the global but inducible removal of the transporter in young mice leads to intestinal loss of Pi and lung calcifications.