Regulation of prostasin by aldosterone in the kidney

Narikiyo, Takefumi; Kitamura, Kenichiro; Adachi, Masataka; Miyoshi, Takuji; Iwashita, Kozo; Shiraishi, Naoki; Nonoguchi, Hiroshi; Chen, Li Mei; Chai, Karl X.; Chao, Julie; Tomita, Kimio

doi:10.1172/jci13229

Cited by 83 publications

(91 citation statements)

References 25 publications

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“…1A, prostasin migrates as 37-and 40-kDa bands in the apical secretions; however, no prostasin was observed in the basolateral secretions. These results are consistent with previous reports of prostasin secretion from human prostate tissue (48) and from various immortalized mouse cell lines (36,45) but differ from a study in the immortalized bronchial epithelial cell line JME/CF15, in which prostasin was not present in the secretions (43). To clarify whether prostasin is secreted in the airway, we also performed Western blotting on sputum from a CF patient (Fig.…”

Section: Prostasin Is Expressed In a Nonpolarized Distribution But Onsupporting

confidence: 91%

Prostasin expression is regulated by airway surface liquid volume and is increased in cystic fibrosis

Myerburg

McKenna²,

Luke³

et al. 2008

American Journal of Physiology-Lung Cellular and Molecular Phys

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Airway surface liquid (ASL) absorption is initiated by Na+ entry via epithelial Na+ channels (ENaC), which establishes an osmotic gradient that drives fluid from the luminal to serosal airway surface. We and others have recently reported that a protease/anti-protease balance regulates ENaC in human airway epithelial cells (HAEC) and provides a mechanism for autoregulation of ASL volume. In cystic fibrosis (CF), this balance is disturbed, leading to constitutive proteolytic activation of ENaC and the pathological Na+ hyperabsorption characteristic of this airway disease. Prostasin is a glycosylphosphatidylinositol-anchored serine protease that activates ENaC and is expressed on the surface epithelium lining the airway. In this report we present evidence that prostasin expression is regulated by the ASL volume, allowing for increased proteolytic activation of ENaC when the ASL volume is high. Prostasin activity is further regulated by the cognate serpin protease nexin-1 (PN-1), which is expressed in HAEC and inhibits Na+ absorption by forming an inactive complex with prostasin and preventing the proteolytic processing of prostasin. Whereas these mechanisms regulate prostasin expression in response to ASL volume in non-CF epithelia, HAEC cultured from CF patients express >50% more prostasin on the epithelial surface. These findings suggest that a proteolytic cascade involving prostasin, an upstream prostasin-activating protease, and PN-1 regulate Na+ absorption in the airway and that abnormal prostasin expression contributes to excessive proteolytic activation of ENaC in CF patients.

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Section: Prostasin Is Expressed In a Nonpolarized Distribution But Onsupporting

confidence: 91%

Prostasin expression is regulated by airway surface liquid volume and is increased in cystic fibrosis

Myerburg

McKenna²,

Luke³

et al. 2008

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…10,11,[14][15][16] Prostasin has been identified as a potential regulator of amiloride-sensitive ENaC function in the kidney, lung and airways. [17][18][19][20][21][22][23] However, the physiological role of this protein remains largely undetermined, although dysregulation of prostasin expression has been found in high-grade human prostate and breast cancers. 14,[24][25][26] Catalytically active prostasin was detected in urine from both men and women.…”

Section: Introductionmentioning

confidence: 99%

“…27 Furthermore, we showed that urinary excretion of prostasin in patients with primary aldosteronism was substantially elevated and normalized after adrenalectomy. 19 Regarding urinary prostasin, Olivieri et al 20 showed that spironolactone increased the urinary Na/K ratio and decreased urinary prostasin level in normotensives in whom the renin-aldosterone axis was activated by a low sodium intake, suggesting the regulation of urinary prostasin by aldosterone. On the contrary, however, one report presented evidence that the expression of prostasin by adenovirus-mediated human prostasin gene delivery resulted in a subsequent increase in aldosterone production and hypertension in rats.…”

Section: Introductionmentioning

confidence: 99%

Urinary prostasin in humans: relationships among prostasin, aldosterone and epithelial sodium channel activity

et al. 2009

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Prostasin, a membrane-bound serine protease, is known to increase the activity of the epithelial sodium channel (ENaC). Gene expression of prostasin was shown to be regulated by aldosterone, which increases the rate of sodium reabsorption through ENaC. To clarify the physiological relationships among prostasin, aldosterone and ENaC, we developed a specific radioimmunoassay (RIA) for human prostasin. Prostasin levels in urine were determined in 26 normotensive and 121 hypertensive subjects. Aldosterone content in urine and plasma, urinary Na/K ratio and other clinical parameters were also measured. We observed a highly significant correlation between prostasin and aldosterone concentration in urine (correlation coefficient: 0.673, Po0.0001). A significant correlation was also found between urinary prostasin and plasma aldosterone concentration (correlation coefficient: 0.229, Po0.05). In addition, urinary prostasin excretion was inversely correlated with urinary Na/K ratio (correlation coefficient: À0.425, Po0.0001). In conclusion, we developed a prostasin-specific RIA and applied it to the clinical study. Our findings suggest that urinary prostasin level is strongly correlated with urinary or plasma aldosterone level and may serve as a surrogate marker for ENaC activation in hypertensive patients. However, it is not clear, at the present time, whether endogenous aldosterone regulates prostasin expression or vice versa.

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“…Cap1 was the first of several membrane-tethered serine proteases found to activate the amiloride-sensitive ENaC in the ASDN (14,15). In aldosteroneinfused animals, the renal expression levels of cap1 were profoundly elevated, accompanied by increases in the CD Na + uptake (16). Despite considerable evidence regarding cap1 regulation of the Na + transport in ASDN, it is not known what role cap1 may play in the Cl − handling.…”

mentioning

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.

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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...

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Regulation of prostasin by aldosterone in the kidney

Cited by 83 publications

References 25 publications

Prostasin expression is regulated by airway surface liquid volume and is increased in cystic fibrosis

Prostasin expression is regulated by airway surface liquid volume and is increased in cystic fibrosis

Urinary prostasin in humans: relationships among prostasin, aldosterone and epithelial sodium channel activity

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

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