Knockout mouse models for intestinal electrolyte transporters and regulatory PDZ adaptors: new insights into cystic fibrosis, secretory diarrhoea and fructose‐induced hypertension

Seidler, Ursula; Singh, Anurag Kumar; Chen, Mingmin; Cinar, Ayhan; Bachmann, Oliver; Zheng, Wei; Wang, Jian; Yeruva, Sunil; Riederer, Brigitte

doi:10.1113/expphysiol.2008.043018

Cited by 32 publications

(28 citation statements)

References 42 publications

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“…Na + , K + , Cl -, and HCO 3 -transport by the gastrointestinal tract and the various segments of the renal tubule controls the absorption and secretion of these ions and thus systemic volume, blood pressure, and pH of biological fluids (1)(2)(3). The transport of these ions is determined by a hierarchy of transporters, including NKCC2, NCCT, KCCT, ENaC, ROMK, and Cl -channels (3)(4)(5). Altered function of these transporters leads to unbalanced Na + and other ion homeostasis and thus hypo-or hypertension and hyperkalemia (3,6).…”

Section: Introductionmentioning

confidence: 99%

“…In the pancreatic and parotid ducts, about 70% of HCO 3 -enters the cells across the basolateral membrane (BLM) through the Na + -HCO 3 -cotransporter identified as pNBC1 (19) (and renamed NBCe1-B; ref. 20), with the remaining 30% provided by the Na + /H + exchanger NHE1 (1,2,4,5). HCO 3 -exits the luminal membrane through the coordinated action of the Cl -channel CFTR and the Cl -/HCO 3 -exchanger SLC26 transporters, most commonly Slc26a6 and Slc26a3 (4).…”

Section: Introductionmentioning

confidence: 99%

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IRBIT governs epithelial secretion in mice by antagonizing the WNK/SPAK kinase pathway

Yang¹,

Li²,

So³

et al. 2011

J. Clin. Invest.

103

175

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

IRBIT governs epithelial secretion in mice by antagonizing the WNK/SPAK kinase pathway

Yang¹,

Li²,

So³

et al. 2011

J. Clin. Invest.

103

175

View full text Add to dashboard Cite

“…The scaffolding-like PDZ proteins have been involved in the regulation of numerous receptor and transporter proteins (41)(42)(43)(44)(45)(46). In the case of the renal Na/P i transporters, NaPi-2a interact with and are susceptible to be regulated by several PDZ proteins including the NHERF family members (NHERF-1, 2, 3, and 4) (12-17), Shank2E (19,47), and CAL (18).…”

Section: Discussionmentioning

confidence: 99%

Role of PDZK1 Protein in Apical Membrane Expression of Renal Sodium-coupled Phosphate Transporters

Giral

Lanzanò

Caldas

et al. 2011

Journal of Biological Chemistry

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The sodium-dependent phosphate (Na/P i ) transporters NaPi-2a and NaPi-2c play a major role in the renal reabsorption of P i . The functional need for several transporters accomplishing the same role is still not clear. However, the fact that these transporters show differential regulation under dietary and hormonal stimuli suggests different roles in P i reabsorption. The pathways controlling this differential regulation are still unknown, but one of the candidates involved is the NHERF family of scaffolding PDZ proteins. We propose that differences in the molecular interaction with PDZ proteins are related with the differential adaptation of Na/P i transporters. Pdzk1 ؊/؊ mice adapted to chronic low P i diets showed an increased expression of NaPi-2a protein in the apical membrane of proximal tubules but impaired up-regulation of NaPi-2c. These results suggest an important role for PDZK1 in the stabilization of NaPi-2c in the apical membrane. We studied the specific protein-protein interactions of Na/P i transporters with NHERF-1 and PDZK1 by FRET. FRET measurements showed a much stronger interaction of NHERF-1 with NaPi-2a than with NaPi-2c. However, both Na/P i transporters showed similar FRET efficiencies with PDZK1. Interestingly, in cells adapted to low P i concentrations, there were increases in NaPi-2c/PDZK1 and NaPi-2a/NHERF-1 interactions. The differential affinity of the Na/P i transporters for NHERF-1 and PDZK1 proteins could partially explain their differential regulation and/or stability in the apical membrane. In this regard, direct interaction between NaPi-2c and PDZK1 seems to play an important role in the physiological regulation of NaPi-2c.The type II sodium-coupled phosphate (Na/P i ) 3 transporters are the molecules responsible for tubular reabsorption of P i and are the target of hormonal and nonhormonal mechanisms that control phosphate homeostasis. NaPi-2a (NaPiIIa) is responsible for ϳ70% of the P i reabsorbed in the adult kidney of mice, whereas NaPi-2c (NaPiIIc) handles the remaining 30% (1, 2). A low dietary P i intake induces an increase of P i reabsorption in the proximal tubule mediated by augmented apical expression of NaPi-2a and NaPi-2c transporters and consequent increased P i uptake (3-6).Despite sharing a very similar molecular structure, NaPi-2a and NaPi-2c exhibit an increasing list of physiological differences. For example, whereas NaPi-2a is electrogenic, NaPi-2c is electroneutral (4, 7). In addition, both transporters participate in the renal adaptation to changes in dietary P i with different characteristics. In response to a high P i intake, NaPi-2a abundance decreases quickly (less than 1 h), internalization takes place in a microtubule-independent way, and molecules are targeted to the lysosomes via endosomes (8, 9). In contrast, under a high P i intake, NaPi-2c abundance decreases slowly (4 h), molecules are internalized through a microtubule-dependent pathway, and rather than being degraded, they are accumulated in a subapical compartment (10). Similar differences...

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“…37) Mice lacking either the Na ϩ /H ϩ exchanger NHE3 72) or the Cl Ϫ /HCO 3 Ϫ exchanger Slc26a3 (DRA) 46) have a significantly reduced intestinal absorptive capacity, which makes these proteins the most likely molecular correlate for NaCl absorption. NHE3 and DRA are not only expressed in the small intestine, where electroneutral NaCl absorption is the most important Na ϩ absorptive pathway in the absence of nutrients, [73][74][75] but also in the proximal colon. 76,77) The classical concept that Na ϩ /H ϩ exchange and Cl Ϫ /HCO 3 Ϫ exchange are coupled by pH changes had been established in brush border membrane vesicles.…”

Section: Electroneutral Nacl Absorption Namentioning

confidence: 99%

News from the End of the Gut-How the Highly Segmental Pattern of Colonic HCO3- Transport Relates to Absorptive Function and Mucosal Integrity

Bachmann

Seidler

2011

Biological & Pharmaceutical Bulletin

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A number of transport mechanisms in the colonic epithelium contribute to HCO 3 ؊ ؊ movement across the apical and basolateral membranes, but this ion has been largely regarded as a by-product of the transport functions it is involved in, such as NaCl-or short chain fatty acid (SCFA) absorption. However, emerging data points to several specific roles of HCO 3 ؊ ؊ for colonic epithelial physiology, including pH control in the colonic surface microenvironment, which is important for transport-and immune functions, as well as the secretion and the rheological properties of the mucus gel. Furthermore, recent studies have demonstrated that colonic HCO 3 ؊ ؊ transporters are expressed in a highly segmental as well as species-specific manner. This review summarizes recently gathered information on the functional anatomy of the colon, the roles of HCO 3 ؊ ؊ in the colonic epithelium, colonic mucosal integrity, and the expression and function of HCO 3 ؊ ؊ transporting mechanisms in health and disease.

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Knockout mouse models for intestinal electrolyte transporters and regulatory PDZ adaptors: new insights into cystic fibrosis, secretory diarrhoea and fructose‐induced hypertension

Cited by 32 publications

References 42 publications

IRBIT governs epithelial secretion in mice by antagonizing the WNK/SPAK kinase pathway

IRBIT governs epithelial secretion in mice by antagonizing the WNK/SPAK kinase pathway

Role of PDZK1 Protein in Apical Membrane Expression of Renal Sodium-coupled Phosphate Transporters

News from the End of the Gut-How the Highly Segmental Pattern of Colonic HCO3- Transport Relates to Absorptive Function and Mucosal Integrity

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