Enhanced phosphate absorption in intestinal epithelial cell‐specific NHE3 knockout mice

Xue, Jianxiang; Thomas, Linto; Murali, Sathish Kumar; Levi, Moshe; Fenton, Robert A.; Rieg, Jessica A Dominguez; Rieg, Timo

doi:10.1111/apha.13756

Cited by 14 publications

(11 citation statements)

References 49 publications

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“…Since mice with deletion of NHE3 selectively in the proximal tubules of the kidney do not develop these intestinal structural abnormalities, and severe diarrhea and Na + wasting phenotypes (see below; Li et al, 2018 , 2019a ), our studies suggest that NHE3 in the gastrointestinal tract may likely play an important role in the development of the gut in addition to its major role in mediating Na + absorption. However, a recently developed, inducible intestine-specific Nhe3 −/− mouse model does not show any intestinal structural abnormalities as Nhe3 −/− or tg Nhe3 −/− mice do ( Xue et al, 2020 , 2022 ). The reasons underlying these differences between global Nhe3 −/− , transgenic tg Nhe3 −/− , and intestine-specific Nhe3 −/− mice remain unknown.…”

Section: Physiological Function Of Gastrointestinal Nhe3 In the Regul...mentioning

confidence: 96%

“…Indeed, diarrhea persisted, and basal blood pressure remained significantly lower in tg Nhe3 −/− mice ( Figure 4 ; Li et al, 2015a ; Zhuo et al, 2021 ). Recently, Xue et al (2020 , 2022) have generated a new inducible intestinal epithelial cell-specific NHE3 knockout mouse model, which showed similar intestinal abnormal absorptive phenotypes, mimicking congenital sodium diarrhea with enhanced phosphate. Thus, the development of moderate to severe diarrhea due to intestinal Na + absorptive defect is a major phenotype in global and intestine-specific Nhe3 −/− mice ( Schultheis et al, 1998a ; Li et al, 2015a , b ; Xue et al, 2020 , 2022 ).…”

Section: Physiological Function Of Gastrointestinal Nhe3 In the Regul...mentioning

confidence: 99%

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The Na+/H+ Exchanger 3 in the Intestines and the Proximal Tubule of the Kidney: Localization, Physiological Function, and Key Roles in Angiotensin II-Induced Hypertension

Nwia

Leite

et al. 2022

Front. Physiol.

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The sodium (Na+)/hydrogen (H+) exchanger 3 (NHE3) is one of the most important Na+/H+ antiporters in the small intestines of the gastrointestinal tract and the proximal tubules of the kidney. The roles of NHE3 in the regulation of intracellular pH and acid–base balance have been well established in cellular physiology using in vitro techniques. Localized primarily on the apical membranes in small intestines and proximal tubules, the key action of NHE3 is to facilitate the entry of luminal Na+ and the extrusion of intracellular H+ from intestinal and proximal tubule tubular epithelial cells. NHE3 is, directly and indirectly, responsible for absorbing the majority of ingested Na+ from small and large intestines and reabsorbing >50% of filtered Na+ in the proximal tubules of the kidney. However, the roles of NHE3 in the regulation of proximal tubular Na+ transport in the integrative physiological settings and its contributions to the basal blood pressure regulation and angiotensin II (Ang II)-induced hypertension have not been well studied previously due to the lack of suitable animal models. Recently, novel genetically modified mouse models with whole-body, kidney-specific, or proximal tubule-specific deletion of NHE3 have been generated by us and others to determine the critical roles and underlying mechanisms of NHE3 in maintaining basal body salt and fluid balance, blood pressure homeostasis, and the development of Ang II-induced hypertension at the whole-body, kidney, or proximal tubule levels. The objective of this invited article is to review, update, and discuss recent findings on the critical roles of intestinal and proximal tubule NHE3 in maintaining basal blood pressure homeostasis and their potential therapeutic implications in the development of angiotensin II (Ang II)-dependent hypertension.

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Section: Physiological Function Of Gastrointestinal Nhe3 In the Regul...mentioning

confidence: 96%

Section: Physiological Function Of Gastrointestinal Nhe3 In the Regul...mentioning

confidence: 99%

The Na+/H+ Exchanger 3 in the Intestines and the Proximal Tubule of the Kidney: Localization, Physiological Function, and Key Roles in Angiotensin II-Induced Hypertension

Nwia

Leite

et al. 2022

Front. Physiol.

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“…In order to unravel such a mechanism we studied inducible intestinal epithelia cell-specific NHE3 knockout mice [46]. Of note, genetic deletion of intestinal NHE3 resulted in enhanced rather than reduced intestinal P i uptake [47 ▪▪ ], implying that different mechanisms/conditions are causing the differences between pharmacological inhibition vs. genetic deletion. Last year the United States Food and Drug Administration denied the approval of tenapanor due to small effect of unclear clinical significance [48]; however, this decision has been appealed by Ardelyx, Inc.…”

Section: Therapeutic Strategies For Lowering Hyperphosphatemia In Chr...mentioning

confidence: 99%

Sodium phosphate cotransporter 2a inhibitors: potential therapeutic uses

Xue¹,

Thomas²,

Rieg

et al. 2022

Current Opinion in Nephrology &Amp; Hypertension

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Purpose of reviewTargeting 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 findingsTwo novel Npt2a-selective inhibitors (PF-06869206 and BAY-767) have been developed. Pharmacological Npt2a inhibition shows a significant phosphaturic effect and consequently lowers plasma Pi and parathyroid hormone (PTH) levels regardless of CKD. However, plasma fibroblast growth factor 23 (FGF23), a master regulator of Pi homeostasis, shows inconsistent responses between these two inhibitors (no effect by PF-06869206 vs. reduction by BAY-767). In addition to the effects on Pi homeostasis, Npt2a inhibition also enhances urinary excretions of Na+, Cl−, and Ca2+, which is recapitulated in animal models with reduced kidney function. The effect of Npt2a inhibition by BAY-767 on vascular calcification has been studied, with positive results showing that oral treatment with BAY-767 (10 mg kg−1) attenuated the increases in plasma Pi and Ca2+ content in the aorta under the setting of vascular calcification induced by a pan-FGF receptor inhibitor. Together, Npt2a inhibition offers a promising therapeutic approach for treating hyperphosphatemia and reducing cardiovascular complications in CKD.SummaryNpt2a inhibition significantly increases urinary Pi excretion and lowers plasma Pi and PTH levels; moreover, it exerts pleiotropic “off-target” effects, providing a novel treatment for hyperphosphatemia and exhibiting beneficial potential for cardiovascular complications in CKD.

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“…The Na + /H + exchanger 3 (NHE3) mediates Na + and fluid absorption in the intestine and reabsorption in the kidney. Knockout of NHE3 selectively in the small intestine and colon of mice results in disruption of intestinal structural integrity, persistent alkaline diarrhea, metabolic acidosis, hyponatremia and hyperkalemia associated with drastically elevated plasma aldosterone levels, and increased mortality rate (Xue et al, 2020;Xue et al, 2022). Together, these symptoms are consistent with patients experiencing congenital sodium diarrhea (CSD).…”

Section: Introductionmentioning

confidence: 95%

Intestine-Specific NHE3 Deletion in Adulthood Causes Microbial Dysbiosis

Xue

Rieg

Thomas

et al. 2022

Front. Cell. Infect. Microbiol.

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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. By using metagenome shotgun sequencing, we determined the effect of inducible intestinal epithelial cell-specific deletion of NHE3 (NHE3IEC-KO) in adulthood on the gut microbiome in mice. Compared with control mice, NHE3IEC-KO mice show a significantly different gut microbiome signature, with an unexpected greater diversity. At the phylum level, NHE3IEC-KO mice showed a significant expansion in Proteobacteria and a tendency for lower Firmicutes/Bacteroidetes (F/B) ratio, an indicator of dysbiosis. At the family level, NHE3IEC-KO mice showed significant expansions in Bacteroidaceae, Rikenellaceae, Tannerellaceae, Flavobacteriaceae and Erysipelotrichaceae, but had contractions in Lachnospiraceae, Prevotellaceae and Eubacteriaceae. At the species level, after removing those with lowest occurrence and abundance, we identified 23 species that were significantly expanded (several of which are established pro-inflammatory pathobionts); whereas another 23 species were found to be contracted (some of which are potential anti-inflammatory probiotics) in NHE3IEC-KO mice. These results reveal that intestinal NHE3 deletion creates an intestinal environment favoring the competitive advantage of inflammophilic over anti-inflammatory species, which is commonly featured in conventional NHE3 knockout mice and patients with IBD. In conclusion, our study emphasizes the importance of intestinal NHE3 for gut microbiota homeostasis, and provides a deeper understanding regarding interactions between NHE3, dysbiosis, and IBD.

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Enhanced phosphate absorption in intestinal epithelial cell‐specific NHE3 knockout mice

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmerc ial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 14 publications

References 49 publications

The Na+/H+ Exchanger 3 in the Intestines and the Proximal Tubule of the Kidney: Localization, Physiological Function, and Key Roles in Angiotensin II-Induced Hypertension

The Na+/H+ Exchanger 3 in the Intestines and the Proximal Tubule of the Kidney: Localization, Physiological Function, and Key Roles in Angiotensin II-Induced Hypertension

Sodium phosphate cotransporter 2a inhibitors: potential therapeutic uses

Intestine-Specific NHE3 Deletion in Adulthood Causes Microbial Dysbiosis

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