Aldosterone and tight junctions: modulation of claudin-4 phosphorylation in renal collecting duct cells

Moellic, Cathy Le; Boulkroun, Sheerazed; González-Núñez, Daniel; Dublineau, Isabelle; Cluzeaud, Françoise; Fay, Michèle; Blot‐Chabaud, Marcel; Farman, Nicolette

doi:10.1152/ajpcell.00314.2005

Cited by 86 publications

(45 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Yamauchi et al (36) and Kahle et al (37) have shown, WNK4, causing the inherited hypertensive disease pseudohypoaldosteronism type II (PHAII) syndrome, selectively increases paracellular Cl -permeability in MDCK cells and phosphorylates claudins, including CLDN4. Aldosterone, the primary blood pressure-regulating hormone, upreguates paracellular Cl -permeability in a rat cortical collecting duct cell line RCCD2 and hyperphosphorylates CLDN4 (38). Although we have not studied the regulation of CLDN4 channel, claudin phosphorylation was demonstrated by Ikari et al (39) to play important roles in targeting claudin-16 to TJ.…”

Section: Discussionmentioning

confidence: 77%

Claudin-4 forms paracellular chloride channel in the kidney and requires claudin-8 for tight junction localization

Hou

Renigunta²,

Yang³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

210

233

View full text Add to dashboard Cite

Tight junctions (TJs) play a key role in mediating paracellular ion reabsorption in the kidney. The paracellular pathway in the collecting duct of the kidney is a predominant route for transepithelial chloride reabsorption that determines the extracellular NaCl content and the blood pressure. However, the molecular mechanisms underlying the paracellular chloride reabsorption in the collecting duct are not understood. Here we showed that in mouse kidney collecting duct cells, claudin-4 functioned as a Cl -channel. A positively charged lysine residue at position 65 of claudin-4 was critical for its anion selectivity. Claudin-4 was observed to interact with claudin-8 using several criteria. In the collecting duct cells, the assembly of claudin-4 into TJ strands required its interaction with claudin-8. Depletion of claudin-8 resulted in the loss of paracellular chloride conductance, through a mechanism involving its recruitment of claudin-4 during TJ assembly. Together, our data show that claudin-4 interacts with claudin-8 and that their association is required for the anion-selective paracellular pathway in the collecting duct, suggesting a mechanism for coupling chloride reabsorption with sodium reabsorption in the collecting duct.C hloride is the predominant extracellular ionic constituent and thereby determines extracellular fluid volume (ECFV) and blood pressure (1-3). Although only responsible for the reabsorption of 2-3% filtered chloride, the aldosterone-sensitive distal nephron (ASDN) plays a vital regulatory role in renal handling of salt, ECFV control, and managing blood pressure (4). The ASDN comprises the distal convoluted tubule (DCT), the connecting tubule (CNT), and the collecting duct. The collecting duct is characterized by a heterogeneous epithelium-the principal cells and intercalated cells (5). Sodium reabsorption in the collecting duct is an active process driven by the basolateral Na + /K + -ATPase; acts through the apical epithelial sodium channel (ENaC) in the principal cell (6); and is responsible for generating the lumen-negative transepithelial potential. This electrogenic transport step creates a favorable electrical driving force for luminal reabsorption of chloride and secretion of potassium and proton. Chloride is transported by two major mechanisms (1). Chloride is actively reabsorbed by an electroneutral Cl − /HCO − exchanger (Slc26a4: pendrin) localized to the apical membrane of the β-type intercalated cell (7). Choride exits this cell via a basolateral Cl − channel (2) and diffuses passively down electrochemical gradients via the paracellular channel in the tight junction (TJ).The TJ is the most apical member of the junctional complex found in vertebrate epithelia responsible for the barrier to movement of ions and molecules between apical and basal compartments, the paracellular pathway (8). TJs are composed of three transmembrane proteins: occludin, claudins, and junctional adhesion molecule (JAM). The claudins (CLDNs) are a 28-member family of tetraspan proteins that range in m...

show abstract

Section: Discussionmentioning

confidence: 77%

Claudin-4 forms paracellular chloride channel in the kidney and requires claudin-8 for tight junction localization

Hou

Renigunta²,

Yang³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

210

233

View full text Add to dashboard Cite

show abstract

“…Because claudin-4 KO animals showed a slower reduction of urinary NaCl excretion but a steeper increase of aldosterone production when placed from a regular to a low-salt diet, aldosterone itself may regulate claudin-4 through cap1, WNK4, or other mechanisms. In a rat CD cell model, Le Moellic et al first demonstrated that aldosterone stimulated claudin-4 protein phosphorylation and paracellular Cl -permeability (45).…”

Section: Discussionmentioning

confidence: 99%

The Cap1–claudin-4 regulatory pathway is important for renal chloride reabsorption and blood pressure regulation

Gong

Yang³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The paracellular pathway through the tight junction provides an important route for transepithelial chloride reabsorption in the kidney, which regulates extracellular salt content and blood pressure. Defects in paracellular chloride reabsorption may in theory cause deregulation of blood pressure. However, there is no evidence to prove this theory or to demonstrate the in vivo role of the paracellular pathway in renal chloride handling. Here, using a tissue-specific KO approach, we have revealed a chloride transport pathway in the kidney that requires the tight junction molecule claudin-4. The collecting duct-specific claudin-4 KO animals developed hypotension, hypochloremia, and metabolic alkalosis due to profound renal wasting of chloride. The claudin-4-mediated chloride conductance can be regulated endogenously by a proteasechannel-activating protease 1 (cap1). Mechanistically, cap1 regulates claudin-4 intercellular interaction and membrane stability. A putative cap1 cleavage site has been identified in the second extracellular loop of claudin-4, mutation of which abolished its regulation by cap1. The cap1 effects on paracellular chloride permeation can be extended to other proteases such as trypsin, suggesting a general mechanism may also exist for proteases to regulate the tight junction permeabilities. Together, we have discovered a theory that paracellular chloride permeability is physiologically regulated and essential to renal salt homeostasis and blood pressure control.chloride channel | epithelium | hypertension C hloride is the most abundant extracellular anion and thereby determines extracellular fluid volume (ECFV) and blood pressure (BP) (1, 2). The kidney plays a vital role in ECFV and BP control through complex regulatory mechanisms acting upon ion channels and transporters located in the aldosterone-sensitive distal nephron (ASDN) (3, 4). The ASDN comprises the distal convoluted tubule (DCT), the connecting tubule (CNT), and the collecting duct (CD). The primary chloride transport mechanism in the DCT is through the thiazide-sensitive Na + /Cl − cotransporter (NCC) to reabsorb Cl − coupled with equal moles of Na + (5). The chloride transport mechanism in the CNT and CD, on the other hand, has been under debate for many years. Recent advances have identified an electroneutral transport pathway for chloride using the Cl − /bicarbonate exchanger (Slc26a4; pendrin) (6) and the Na + -driven Cl − /bicarbonate exchanger (Slc4a8; NDCBE) (7) in the β-intercalated cells (ICs) of CNT and CD. However, such an electroneutral pathway is not able to couple Cl − reabsorption with epithelial sodium channel (ENaC)-based Na + reabsorption that takes place in the principal cells (PCs) of CNT and CD (8), despite many efforts to connect ENaC and pendrin gene expression through endocrine or paracrine mechanisms (9, 10). We and others have previously demonstrated the presence of a paracellular Cl − pathway or "chloride shunt" in vitro in the CNT and CD cells (11,12). The paracellular Cl − channel is made of a key claud...

show abstract

“…Aldosterone regulation of claudin-4 was examined in the cortical collecting duct cell line RCCD2 (67). Aldosterone was found to induce phosphorylation of claudin-4 at threonine residues within 20 min, and this was associated with decreased TER and increased 125 I flux, suggesting that the anion permeability of claudin-4 may have been stimulated.…”

Section: Phosphorylation Of Claudinsmentioning

confidence: 99%

Biology of claudins

Angelow¹,

Ahlstrom²,

Yu³

2008

American Journal of Physiology-Renal Physiology

304

294

View full text Add to dashboard Cite

Claudins are a family of tight junction membrane proteins that regulate paracellular permeability of epithelia, likely by forming the lining of the paracellular pore. Claudins are expressed throughout the renal tubule, and mutations in two claudin genes are now known to cause familial hypercalciuric hypomagnesemia with nephrocalcinosis. In this review, we discuss recent advances in our understanding of the physiological role of various claudins in normal kidney function, and in understanding the fundamental biology of claudins, including the molecular basis for selectivity of permeation, claudin interactions in tight junction formation, and regulation of claudins by protein kinases and other intracellular signals.

show abstract

Aldosterone and tight junctions: modulation of claudin-4 phosphorylation in renal collecting duct cells

Cited by 86 publications

References 40 publications

Claudin-4 forms paracellular chloride channel in the kidney and requires claudin-8 for tight junction localization

Claudin-4 forms paracellular chloride channel in the kidney and requires claudin-8 for tight junction localization

The Cap1–claudin-4 regulatory pathway is important for renal chloride reabsorption and blood pressure regulation

Biology of claudins

Contact Info

Product

Resources

About