Genetically determined chloride-sensitive hypertension and stroke

Tanaka, Masae; Schmidlin, Olga; Sl, Yi; Aw, Bollen; Rc, Morris

doi:10.1073/pnas.94.26.14748

Cited by 43 publications

(46 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…De-ionized drinking water was supplied ad libitum. All groups were fed and housed as before 18 and studied according to the guidelines of the University of California, San Francisco, Committee on Animal Research.…”

Section: Methodsmentioning

confidence: 99%

“…3,6 -14 Yet, in the spontaneously hypertensive rat (SHR), 15 selective Cl Ϫ loading with glycine and choline chloride combined induced an exacerbation of hypertension but also an apparent systemic toxicity that complicated its interpretation. 16 In the more salt-sensitive genetic substrain of the SHR, the stroke-prone SHR (SHRSP), 17 selective Cl Ϫ loading with KCl exacerbated hypertension and microangiopathic nephropathy and induced numerous strokes, 18,19 much as does NaCl loading, 20 but not NaHCO 3 loading. 12 Thus, in the SHRSP, the Cl Ϫ component of dietary NaCl might dominantly determine the expression of salt sensitivity.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Chloride-Dominant Salt Sensitivity in the Stroke-Prone Spontaneously Hypertensive Rat

et al. 2005

Self Cite

View full text Add to dashboard Cite

Abstract-We tested the hypothesis that in the stroke-prone spontaneously hypertensive rat (SHRSP), the Cl Ϫ component of dietary NaCl dominantly determines its pressor effect (salt-sensitivity). We telemetrically measured systolic aortic blood pressure (SBP) in SHRSP loaded with: nothing (CTL); NaCl alone (NaCl) (44 mmol/100 grams chow); KCl (KCl) alone (44 mmol); NaCl (44 mmol) combined with KHCO 3 (77 mmol) (NaCl/KBC) or with KCl (77 mmol) (NaCl/KCl). Across all groups, from age 10 to 15 or 16 weeks, SBP increased linearly (mm Hg/week) (dp/dt, change in SBP as a function of time): CTL, 5.6; NaCl, 9.5; KCl, 8.8; NaCl/KBC, 9.1; and NaCl/KCl, 14.6. Thus, the value of dp/dt in KCl matched that in NaCl. The value of dp/dt in NaCl/KCl exceeded that in NaCl in direct proportion to the greater Cl Ϫ load. Across all groups, only Cl Ϫ load bore a direct, highly linear relationship with dp/dt. Strokes occurred only, but always with SBP Ͼ250 mm Hg, a value observed almost exclusively in NaCl/KCl. Thus, Cl Ϫ dominantly determined the pressor effect induced with dietary NaCl, both with NaCl loaded alone and combined with either KCl or KHCO 3 , and thereby likely determined the occurrence of stroke with NaCl loading. Over the initial 3-day period of NaCl loading and exacerbating hypertension, external balance of Na ϩ increased similarly among all groups. However, within 24 hours of initiating NaCl loading, urinary creatinine excretion decreased in direct proportion to dp/dt and urinary Cl Ϫ excretion. We conclude that in the SHRSP, the Cl Ϫ component of a dietary NaCl dominantly determines salt sensitivity and thereby phenotypic expression. We suggest that Cl

show abstract

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Chloride-Dominant Salt Sensitivity in the Stroke-Prone Spontaneously Hypertensive Rat

et al. 2005

Self Cite

View full text Add to dashboard Cite

show abstract

“…Ϫ is necessary for Na ϩ to exert its pressor effect (3)(4)(5)(6)(7), and primary alteration in distal Cl Ϫ transport may have consequences on BP (8 -10). Remarkably, in the CNT and the CD, Na ϩ reabsorption is not linked molecularly to Cl Ϫ transport directly.…”

Section: CLmentioning

confidence: 99%

Pendrin Regulation in Mouse Kidney Primarily Is Chloride-Dependent

Vallet

Picard²,

Loffing‐Cueni³

et al. 2006

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

Recent studies indicate that pendrin, an apical Cl ؊ /HCO 3 ؊ exchanger, mediates chloride reabsorption in the connecting tubule and the cortical collecting duct and therefore is involved in extracellular fluid volume regulation. The purpose of this study was to test whether pendrin is regulated in vivo primarily by factors that are associated with changes in renal chloride transport, by aldosterone, or by the combination of both determinants. For achievement of this goal, pendrin protein abundance was studied by semiquantitative immunoblotting in different mouse models with altered aldosterone secretion or tubular chloride transport, including NaCl loading, hydrochlorothiazide administration, NaCl co-transporter knockout mice, and mice with Liddle's mutation. The parallel regulation of the aldosterone-regulated epithelial sodium channel (ENaC) was examined as a control for biologic effects of aldosterone. Major changes in pendrin protein expression were found in experimental models that are associated with altered renal chloride transport, whereas no significant changes were detected in pendrin protein abundance in models with altered aldosterone secretion. Moreover, in response to hydrochlorothiazide administration, pendrin was downregulated despite a marked secondary hyperaldosteronism. In contrast, ␣-ENaC was markedly upregulated, and the molecular weight of a large fraction of ␥-ENaC subunits was shifted from 85 to 70 kD, consistent with previous results from rat models with elevated plasma aldosterone levels. These results suggest that factors that are associated with changes in distal chloride delivery govern pendrin expression in the connecting tubule and cortical collecting duct.

show abstract

“…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).…”

mentioning

confidence: 99%

“…ion channel | chloride shunt | blood pressure | siRNA | protein interaction C hloride is the predominant extracellular ionic constituent and thereby determines extracellular fluid volume (ECFV) and blood pressure (1)(2)(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).…”

mentioning

confidence: 99%

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.

203

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

Genetically determined chloride-sensitive hypertension and stroke

Cited by 43 publications

References 43 publications

Chloride-Dominant Salt Sensitivity in the Stroke-Prone Spontaneously Hypertensive Rat

Chloride-Dominant Salt Sensitivity in the Stroke-Prone Spontaneously Hypertensive Rat

Pendrin Regulation in Mouse Kidney Primarily Is Chloride-Dependent

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

Contact Info

Product

Resources

About