The Cystic Fibrosis Transmembrane Regulator (CFTR) in the kidney

Abstract

The cystic fibrosis transmembrane regulator (CFTR) is a Cl − channel. Mutations of this transporter lead to a defect of chloride secretion by epithelial cells causing the Cystic Fibrosis disease (CF). In spite of the high expression of CFTR in the kidney, patients with CF do not show major renal dysfunction, but it is known that both the urinary excretion of drugs and the renal capacity to concentrate and dilute urine is deficient. CFTR mRNA is expressed in all nephron segments and its protein is involved with chloride secretion in the distal tubule, and the principal cells of the cortical (CCD) and medullary (IMCD) collecting ducts. Several studies have demonstrated that CFTR does not only transport Cl − but also secretes ATP and, thus, controls other conductances such as Na + (ENaC) and K + (ROMK2) channels, especially in CCD. In the polycystic kidney the secretion of chloride through CFTR contributes to the cyst enlargement. This review is focused on the role of CFTR in the kidney and the implications of extracellular volume regulators, such as hormones, on its function and expression.

Early Embryonic Renal Tubules of Wild-Type and Polycystic Kidney Disease Kidneys Respond to cAMP Stimulation with Cystic Fibrosis Transmembrane Conductance Regulator/Na+,K+,2Cl− Co-Transporter–Dependent Cystic Dilation

“…In contrast to the adult kidney, less is known about the development of tubular transport mechanisms in the embryonic kidney. The expression of CFTR has been demonstrated in the developing tubules of embryonic kidneys, including the early proximal tubules and ureteric buds, and in all nephron segments later in renal development (17,(21)(22)(23)(24)(25)(26). Recently, NKCC1 transcripts were shown by in situ hybridization to be expressed in early embryonic kidneys (45).…”

“…A driving force for fluid secretion during cyst growth is thought to be cAMP-dependent transepithelial Cl Ϫ transport that involves activation of CFTR Cl Ϫ channels that are located on the apical surface of cyst-lining epithelial cells (12,13,(17)(18)(19)(20)(21). In consideration of this, a potential therapeutic intervention for ADPKD is the use of cAMP antagonists (55), which would be expected to slow fluid secretion, as well as cell proliferation, and thereby slow cyst expansion.…”

“…Cultured epithelial cells from cysts of ADPKD kidneys secrete fluid in response to cAMP-driven transepithelial Cl Ϫ transport that is mediated by cystic fibrosis transmembrane conductance regulator (CFTR) (12,13,(17)(18)(19)(20)(21). However, the extent to which cyst formation depends on CFTR and whether CFTR is functional in embryonic kidneys at a time when cyst growth begins in PKD has not been known.…”

“…The expression of CFTR isoforms has been demonstrated by reverse transcriptase-PCR and immunohistochemistry in developing epithelial structures of embryonic kidneys, including the early proximal tubule and ureteric bud (22)(23)(24)(25). Later in development and in the mature kidney, CFTR has been found in all nephron segments (17,21,22,25,26). The functional role of CFTR in the kidney is unclear, because patients with cystic fibrosis (CF) do not seem to have significantly impaired renal function (21,25,26).…”

“…Later in development and in the mature kidney, CFTR has been found in all nephron segments (17,21,22,25,26). The functional role of CFTR in the kidney is unclear, because patients with cystic fibrosis (CF) do not seem to have significantly impaired renal function (21,25,26). However, CFTR-dependent fluid secretion may be a factor in PKD, because patients who have both CF and PKD seem to have somewhat milder cystic disease (27,28).…”