III The Role of Pendrin in the Kidney

Pendrin and Its Partners in the Kidney: Roles in Vascular Volume and Acid Base Regulation

Manoocher Soleimani and Giovanna Valenti

Abstract

The Cl-/HCO3- exchanger pendrin (SLC26A4, PDS) is located on the apical membrane of B-intercalated cells in the kidney cortical collecting duct (CCD) and the connecting tubules (CNTs) and mediates the secretion of bicarbonate and the reabsorption of chloride. Recent studies demonstrate the coordinated interaction of pendrin with several ion transporters and/or channels in the kidney distal nephron, resulting in systemic electrolyte and vascular volume homeostasis and acid base regulation. In this chapter, we will discuss the latest developments on the role of pendrin and its interacting partners in salt and water absorption in the distal nephron and their relevance to pathophysiologic states.

Introduction

The solute carrier (SLC) 26 family of anion transporters comprises both electrogenic and electroneutral chloride/base exchangers that are expressed in various epithelia and polarized cells (SindiC et al. 2007; Soleimani 2013). This family is genetically distinct from the SLC4 anion exchangers (AE1, AE2, AE3, and AE4) and comprises at least ten distinct members (SLC26A1-11) (Sindic et al. 2007; Soleimani 2013; Alper and Sharma 2013). Modes of transport mediated by SLC26 members include the exchange of chloride for bicarbonate, hydroxyl, sulfate, formate, iodide, or oxalate with variable

M. Soleimani, MD (*)

Department of Medicine, University of Cincinnati, Cincinnati, OH, USA e-mail: This email address is being protected from spam bots, you need Javascript enabled to view it ; This email address is being protected from spam bots, you need Javascript enabled to view it

G. Valenti, PhD (*)

Department of Biosciences, Biotechnologies and Biopharmaceutics,

University of Bari, Bari, Italy e-mail: This email address is being protected from spam bots, you need Javascript enabled to view it

© Springer International Publishing Switzerland 2017 121

S. Dossena, M. Paulmichl (eds.), The Role of Pendrin in Health and Disease,

DOI 10.1007/978-3-319-43287-8_8

specificity (Melvin et al. 1999; Soleimani et al. 2001; Jiang et al. 2002; Xie et al. 2002; Chernova et al. 2005; Wang et al. 2002; Schweinfest et al. 2006; Petrovic et al. 2003; Xu et al. 2005, 2008, 2011). Several SLC26 family members can specifically function as Cl-/HCO3- exchangers. These include SLC26A3 (DRA), SLC26A4 (pen- drin), SLC26A6 (PAT1 or CFEX), SLC26A7, SLC26A9, and SLC26A11 (Melvin et al. 1999; Soleimani et al. 2001; Jiang et al. 2002; Xie et al. 2002; Chernova et al. 2005; Wang et al. 2002; Schweinfest et al. 2006; Petrovic et al. 2003; Xu et al. 2005, 2008, 2011). In addition to mediating chloride/base exchange, SLC26A7, SLC26A9, and SLC26A11 can also function as chloride channels (Bertrand et al. 2009; Kim et al. 2005; Dorwart et al. 2007).

Mutations in several SLC26 isoforms are linked to autosomal recessive genetic disorders, with SLC26A2 associated with chondrodysplasias (Hastbacka et al. 1994), SLC26A3 linked to chloride-losing diarrhea (Hoglund et al. 1996), and SLC26A4 connected to Pendred syndrome and nonsyndromic hereditary deafness (Everett et al. 1997). These findings confirm the intriguing and important roles of SLC26 isoforms in normal physiology and human pathophysiology. The generation of genetically engineered mouse models has significantly increased our understanding of the pathophysiology of genetic disorders linked to SLC26 isoforms. These models have further established the important role of SLC26 isoforms in the normal physiology of various organs, including the kidney.

The SLC26A4 gene was first discovered by positional cloning studies in patients with Pendred syndrome (Everett et al. 1997), an autosomal recessive inherited disorder characterized by congenital deafness and thyroid goiter (Bizhanova and Kopp 2010). Pendrin is abundantly expressed in the thyroid and inner ear (Everett et al. 1997), with lower levels in the whole kidney (Bizhanova and Kopp 2010). Pendrin can function in Cl-/HCO3- exchange, Cl-/OH- exchange, and Cl-/I- exchange modes (Soleimani et al. 2001; Royaux et al. 2001); however, its dominant role in the kidney is the mediation of Cl-/HCO3- exchange. Immunofluorescence studies localized pendrin to the apical membrane of B and non-A-, non-B-intercalated cells in the connecting tubule (CNT) and the cortical collecting duct (CCD) (Royaux et al. 2001; Kim et al. 2002; Wall et al. 2003). The schematic diagram in Fig. 8.1 depicts the major salt-absorbing transporters in the distal nephron, including the Cl-/HCO3- exchanger pendrin. This chapter focuses on the latest advances on the role of pendrin in the kidney physiology, as derived from studies on genetically engineered mouse models, humans with Pendred syndrome, and functional and localization experiments.

 
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