The sodium/proton exchanger isoform 3 (NHE3) is expressed in the intestine and the kidney where it facilitates sodium (re)absorption and proton secretion. The importance of NHE3 in the kidney for sodium chloride homeostasis, relative to the intestine, is unknown. Constitutive tubule-specific NHE3 knockout mice (NHE3loxloxCre) did not show significant differences compared to control mice in body weight, blood pH or bicarbonate and plasma sodium, potassium or aldosterone levels. Fluid intake, urinary flow rate, urinary sodium/creatinine and pH were significantly elevated in NHE3loxloxCre mice while urine osmolality and GFR were significantly lower. Water deprivation revealed a small urinary concentrating defect in NHE3loxloxCre mice on a control diet; exaggerated on low sodium chloride. Ten days of low or high sodium chloride diet did not affect plasma sodium in control mice; however, NHE3loxloxCre mice were susceptible to low sodium chloride (about −4 mM) or high sodium chloride intake (about +2 mM) versus baseline, effects without differences in plasma aldosterone between groups. Blood pressure was significantly lower in NHE3loxloxCre mice and was sodium chloride-sensitive. In control mice, the expression of the sodium/phosphate co-transporter Npt2c was sodium chloride-sensitive. However, lack of tubular NHE3 blunted Npt2c expression. Alterations in the abundances of sodium/chloride cotransporter and its phosphorylation at threonine 58 as well as the abundances of the α-subunit of the epithelial sodium channel, and its cleaved form, were also apparent in NHE3loxloxCre mice. Thus, renal NHE3 is required to maintain blood pressure and steady state plasma sodium levels when dietary sodium chloride intake is modified.
BackgroundThe 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. The sodium-phosphate cotransporter Npt2a, which mediates a large proportion of phosphate reabsorption in the kidney, might be a good therapeutic target for new medications for hyperphosphatemia.MethodsThe authors assessed the effects of the first orally bioavailable Npt2a inhibitor (Npt2a-I) PF-06869206 in normal mice and mice that had undergone subtotal nephrectomy (5/6 Nx), a mouse model of CKD. Dose-response relationships of sodium, chloride, potassium, phosphate, and calcium excretion were assessed in response to the Npt2a inhibitor in both groups of mice. Expression and localization of Npt2a/c and levels of plasma phosphate, calcium, parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF-23) were studied up to 24-hours after Npt2a-I treatment.ResultsIn normal mice, Npt2a inhibition caused a dose-dependent increase in urinary phosphate (ED50 approximately 21 mg/kg), calcium, sodium and chloride excretion. In contrast, urinary potassium excretion, flow rate and urinary pH were not affected dose dependently. Plasma phosphate and PTH significantly decreased after 3 hours, with both returning to near baseline levels after 24 hours. Similar effects were observed in the mouse model of CKD but were reduced in magnitude.ConclusionsNpt2a inhibition causes a dose-dependent increase in phosphate, sodium and chloride excretion associated with reductions in plasma phosphate and PTH levels in normal mice and in a CKD mouse model.
IntroductionProbiotic use to prevent nosocomial gastrointestinal and potentially respiratory tract infections in critical care has shown great promise in recent clinical trials of adult and pediatric patients. Despite well-documented benefits of probiotic use in intestinal disorders, the potential for probiotic treatment to reduce lung injury following infection and shock has not been well explored.ObjectiveEvaluate if Lactobacillus rhamnosus GG (LGG) or Bifidobacterium longum (BL) treatment in a weanling mouse model of cecal ligation and puncture (CLP) peritonitis will protect against lung injury.Methods3 week-old FVB/N mice were orally gavaged with 200 µl of either LGG, BL or sterile water (vehicle) immediately prior to CLP. Mice were euthanized at 24 h. Lung injury was evaluated via histology and lung neutrophil infiltration was evaluated by myeloperoxidase (MPO) staining. mRNA levels of IL-6, TNF-α, MyD88, TLR-4, TLR-2, NFΚB (p50/p105) and Cox-2 in the lung analyzed via real-time PCR. TNF-α and IL-6 in lung was analyzed via ELISA.ResultsLGG and BL treatment significantly improved lung injury following experimental infection and sepsis and lung neutrophil infiltration was significantly lower than in untreated septic mice. Lung mRNA and protein levels of IL-6 and TNF-α and gene expression of Cox-2 were also significantly reduced in mice receiving LGG or BL treatment. Gene expression of TLR-2, MyD88 and NFΚB (p50/p105) was significantly increased in septic mice compared to shams and decreased in the lung of mice receiving LGG or BL while TLR-4 levels remained unchanged.ConclusionsTreatment with LGG and BL can reduce lung injury following experimental infection and sepsis and is associated with reduced lung inflammatory cell infiltrate and decreased markers of lung inflammatory response. Probiotic therapy may be a promising intervention to improve clinical lung injury following systemic infection and sepsis.
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. To navigate this problem and better understand the role of intestinal NHE3, we generated a tamoxifen-inducible intestinal epithelial cell-specific NHE3 knockout mouse model (NHE3IEC-KO). Before tamoxifen administration, the phenotype and blood parameters of NHE3IEC-KO were unremarkable compared with control mice. After tamoxifen administration, NHE3IEC-KO mice have undetectable levels of NHE3 in the intestine. NHE3IEC-KO mice develop watery, alkaline diarrhea in combination with a swollen small intestine, cecum and colon. The persistent diarrhea results in higher fluid intake. After 3 weeks, NHE3IEC-KO mice show a ∼25% mortality rate. The contribution of intestinal NHE3 to acid–base and Na+ homeostasis under normal conditions becomes evident in NHE3IEC-KO mice that have metabolic acidosis, lower blood bicarbonate levels, hyponatremia and hyperkalemia associated with drastically elevated plasma aldosterone levels. These results demonstrate that intestinal NHE3 has a significant contribution to acid–base, Na+ and volume homeostasis, and lack of intestinal NHE3 has consequences on intestinal structural integrity. This mouse model mimics and explains the phenotype of individuals with CSD carrying SLC9A3 mutations.
Epithelial glucose transport is accomplished by Na + -glucose co-transporters, SGLT1 and SGLT2.In the intestine, uptake of dietary glucose is for its majority mediated by SGLT1, and humans with mutations in the SGLT1 gene show glucose/galactose malabsorption. In the kidney, both transporters, SGLT1 and SGLT2, are expressed and recent studies identified that SGLT2 mediates up to 97% of glucose reabsorption. Humans with mutations in the SGLT2 gene show familial renal glucosuria. In the last three decades, significant progress was made in understanding the physiology of these transporters and their potential as therapeutic targets. Based on the structure of phlorizin, a natural compound acting as a SGLT1/2 inhibitor, initially several SGLT2, and later SGLT1 and dual SGLT1/2 inhibitors have been developed. Interestingly, SGLT2 knockout or treatment with SGLT2 selective inhibitors only causes a fractional glucose excretion in the magnitude of $60%, an effect mediated by up-regulation of renal SGLT1. Based on these findings the hypothesis was brought forward that dual SGLT1/2 inhibition might further improve glycaemic control via targeting two distinct organs that express SGLT1: the intestine and the kidney. Of note, SGLT1/2 double knockout mice completely lack renal glucose reabsorption. This review will address the rationale for the development of SGLT1 and dual SGLT1/2 inhibitors and potential benefits compared to sole SGLT2 inhibition. K E Y W O R D Schronic kidney disease, drug development, heart failure, inhibitor, intestinal glucose transport, renal glucose transport, sodium-glucose cotransporter, type 1 diabetes, type 2 diabetes
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