Physiological roles and molecular mechanisms of K+ -Cl- cotransport in the mammalian kidney and cardiovascular system: where are we?

Abstract

In the early 80s, renal microperfusion studies led to the identification of a basolateral K⁺ -Cl^- cotransport mechanism in the proximal tubule, thick ascending limb of Henle and collecting duct. More than ten years later, this mechanism was found to be accounted for by three different K⁺ -Cl^- cotransporters (KCC1, KCC3 and KCC4) that are differentially distributed along the renal epithelium. Two of these isoforms (KCC1 and KCC3) were also found to be expressed in arterial walls, the myocardium and a variety of neurons. Subsequently, valuable insights have been gained into the molecular and physiological properties of the KCCs in both the mammalian kidney and cardiovascular system. There is now robust evidence indicating that KCC4 sustains distal renal acidification and that KCC3 regulates myogenic tone in resistance vessels. However, progress in understanding the functional significance of these transporters has been slow, probably because each of the KCC isoforms is not identically distributed among species and some of them share common subcellular localizations with other KCC isoforms or sizeable conductive Cl^- pathways. In addition, the mechanisms underlying the process of K⁺ -Cl^- cotransport are still ill defined. The present review focuses on the knowledge gained regarding the roles and properties of KCCs in renal and cardiovascular tissues.

Keywords: Animal models; Cardiovascular system; Cation-Cl− cotransporter; K+-Cl− cotransporter; Renal tubular acidosis; Systemic hypertension.

Figure 1

Cladogram of human CCC family members The tree was generated with Clustal Omega and FigTree v1.4.3. Amino acid sequences included in the phylogenetic analysis were from the most abundant CCC variants in human. Accession numbers used: NKCC1, NP_001037.1; NKCC2, NP_000329.2; NCC, NP_000330.2; KCC1, NP_005063.1; KCC2, NP_001128243.1; KCC3, NP_598408.1; KCC4, NP_006589.2; CCC8, NP_064631.2; CCC9, NP_078904.3.

Figure 2

Topological models of NKCC1, KCC3 and KCC4 The models were generated with PLOT (Biff Forbush, Yale University). Each glycosylation site is illustrated through a branched line and each residue through a single symbol. Yellow is used to designate well‐characterized phosphoacceptor residues and light blue a protein segment that comes in three variants from alternative splicing of the primary transcript.

Figure 3

Role of K⁺‐Cl⁻ cotransport in the mammalian nephron A, proximal nephron. Ion transport systems shown correspond to a KCC, AQP1 and the Na⁺/K⁺‐ATPase on the basolateral membrane and to a Cl⁻‐dependent carrier (such as SLC26A6), AQP1 and a Na⁺‐dependent carrier (such as SGLT2) on the apical membrane. B, thick ascending limb of Henle. Ion transport systems shown correspond to a Cl⁻ channel, a KCC and the Na⁺/K⁺‐ATPase on the basolateral membrane and to NKCC2 and KCNJ1 on the apical membrane. C, collecting duct (α‐IC cell). Ion transport systems shown correspond to SLC4A1 (Cl⁻/HCO₃ ⁻ exchanger) or SLC26A7 (Cl⁻/A⁻ exchanger) and two KCCs on the basolateral membrane and to vacuolar H⁺‐ATPase on the apical membrane. Note that a H⁺/K⁺‐ATPase is also present on the apical membrane but is not shown. Red is used to indicate net secretion or absorption of the substrates. Abbreviations: A⁻, anion including HCO₃ ⁻, OH⁻, SO₄ ⁻² and oxalate⁻²; Glu, glucose.

Figure 4

Role of K⁺‐Cl⁻ cotransport in arterial VSMCs Ion transport systems shown correspond to KCC3, Ca²⁺‐activated Cl⁻ channel (CACC), SLC8A1 (Na⁺/Ca²⁺ exchanger or NCX type 1), L‐type voltage‐sensitive Ca²⁺ channel (Ca_v1) and SLC4A1 or SLC26A7. Increased KCC3 activity promotes Cl⁻ entry (or decrease Cl⁻ exit) through CACC and, secondarily, anion exchange by SLC4A1 or SLC26A7. It should therefore decrease membrane potential as well as intracellular pH, and thereby stimulate Na⁺/Ca²⁺ exchange by NCX1 and inhibit Ca²⁺ movement through Ca_v1. The end‐result of increased KCC3 activity should thus be a decrease in [Ca²⁺]_i and, secondarily, in myogenic tone.