Disease relevance of Slc26a4

• Thus genetic disruption of Slc26a4 leads to systemic alkalosis in some treatment models [1].
• Following treatment with aldosterone analogues, e.g. deoxycorticosterone pivalate (DOCP), weight gain and hypertension are observed in Slc26a4+/+ but not in Slc26a4-/- mice [2].
• Pendred's syndrome is an autosomal-recessive disorder characterized by deafness and goiter [3].
• Consistent with the altered strial morphology, the endocochlear potential in Pds-/- mice was near zero and did not change during anoxia [4].
• In the absence of DOCP, arterial pH, systolic blood pressure, and body weight were similar in Pds (+/+) and Pds (-/-) mice [5].

High impact information on Slc26a4

• We now report the cDNA cloning of CFEX, a mouse pendrin homolog with expression in the kidney by Northern analysis [6].
• This highly discrete expression pattern is unlike that of any other known gene and involves several regions thought to be important for endolymphatic fluid resorption in the inner ear, consistent with the putative functioning of pendrin as an anion transporter [3].
• Pds expression was detected throughout the endolymphatic duct and sac, in distinct areas of the utricle and saccule, and in the external sulcus region within the cochlea [3].
• In situ hybridization of Foxi1(-/-) endolymphatic duct/sac epithelium shows a complete lack of the transcript encoding the chloride/iodide transporter pendrin [7].
• These results suggest that factors that are associated with changes in distal chloride delivery govern pendrin expression in the connecting tubule and cortical collecting duct [8].

Chemical compound and disease context of Slc26a4

• We conclude that pendrin is upregulated with aldosterone analogues and is critical in the pathogenesis of mineralocorticoid-induced hypertension and metabolic alkalosis [5].
• Moreover, in response to hydrochlorothiazide administration, pendrin was downregulated despite a marked secondary hyperaldosteronism [8].
• Instead, the goiter associated with ClC-5 KO results from impaired rate of apical iodide efflux by down-regulation of pendrin expression [9].

Biological context of Slc26a4

• However, humans and mice with genetic disruption of Slc26a4 have normal acid-base balance under basal conditions [1].
• Thus, Slc26a4 expression and its role in blood pressure and fluid and electrolyte homeostasis was explored during NaCl restriction, a treatment model in which aldosterone is appropriately increased [10].
• Moreover, Slc26a4(-/-) mice had evidence of relative vascular volume depletion because they had a higher arterial pH, hematocrit, and blood urea nitrogen than wild-type mice [10].
• Functional studies were also performed to examine the role of pendrin in endolymph homeostasis [4].
• This suggests a possible role for pendrin in cationic ion transport required to maintain the physiological function of the endometrium [11].

Anatomical context of Slc26a4

• With moderate physiological NaCl restriction, Slc26a4 expression in the apical plasma membrane increased 2- to 3-fold in type B intercalated cells [10].
• Endolymph volume in Slc26a4-/- mice was increased and tissue masses in areas normally occupied by type I and II fibrocytes were reduced [12].
• Lack of pendrin expression leads to deafness and expansion of the endolymphatic compartment in inner ears of Foxi1 null mutant mice [7].
• In type B intercalated cells, pendrin immunoreactivity was highest in apical cytoplasmic vesicles with little immunolabel along the apical plasma membrane [13].
• BACKGROUND: Pendrin belongs to a superfamily of Cl-/anion exchangers and is expressed in the inner ear, the thyroid gland, and the kidney [14].

Associations of Slc26a4 with chemical compounds

• However, urinary pH and Pco(2) were much lower in Slc26a4 null relative to wild-type mice due to reduced urinary buffering of secreted H(+) by HCO(3)(-) [1].
• Excretion of ammonium, titratable acid, and citrate were the same in Slc26a4 null and wild-type mice [1].
• Deoxycorticosterone upregulates PDS (Slc26a4) in mouse kidney: role of pendrin in mineralocorticoid-induced hypertension [5].
• Moreover, during NaCl restriction or following DOCP treatment, Slc26a4-/- mice have a higher serum HCO3- than wild type mice from an impaired ability to excrete OH- equivalents [2].
• Pendrin is the protein product of the PDS gene (SLC26A4) and functions in several different anion exchange modes, including chloride/formate exchange [15].

Regulatory relationships of Slc26a4

• Pendrin- and vH+-ATPase-positive cells also expressed cytoplasmic CA II [16].

Other interactions of Slc26a4

• Co-expression of pendrin, vacuolar H+-ATPase alpha4-subunit and carbonic anhydrase II in epithelial cells of the murine endolymphatic sac [16].
• Here we investigated the expression patterns of acid-base regulators, including vacuolar (v)H+-ATPase (proton pump), carbonic anhydrase (CA) II, and pendrin in the murine ES epithelium by immunohistochemistry (IHC) and compared their expression patterns by double immunostaining [16].
• In the ICT and CCD, basolateral RhBG immunoreactivity is also present in A-type intercalated cells but not in pendrin-positive CCD intercalated cells [17].
• The prolactin effect on iodide uptake into cultured mammary tissues was abolished by pendrin transport inhibitors, including DIDS, furosemide, and probenecid [18].

Analytical, diagnostic and therapeutic context of Slc26a4

• To answer these questions, net acid excretion and H(+)/OH(-) transporter expression were examined in Slc26a4 (-/-) and Slc26a4 (+/+) mice using balance studies, immunolocalization, and immunoblotting [1].
• Immunohistochemistry and confocal laser scanning microscopy demonstrated the presence of pendrin in apical domains of all type B intercalated cells in mouse and rat connecting tubule and collecting duct [19].
• Immunoelectron microscopy demonstrated that pendrin was located in the apical plasma membrane and intracellular vesicles of both type B intercalated cells and non-A-non-B cells; the latter was identified by the presence of H(+)-ATPase in the apical plasma membrane [19].
• A deer mouse-specific partial pendrin cDNA sequence was generated, from which Taqman-specific probe and primers were designed for quantification of mRNA equivalents of pendrin gene expression using real-time polymerase chain reaction (PCR) [20].

References