Distal Convoluted Tubule

McCormick, James A.; Ellison, David H.

doi:10.1002/cphy.c140002

Cited by 72 publications

(95 citation statements)

References 575 publications

(939 reference statements)

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“…A study in mice (46) found that administration of the NCC blocker hydrochlorothiazide to WT mice did not increase kaliuresis acutely. The Welling group recently generated a mouse model with constitutive activation of SPAK specifically along the DCT1 (47), which exclusively expresses NCC, in contrast to the DCT2, which -in common with the connecting tubule (CNT) -also expresses the ENaC and ROMK (48). These mice displayed remodeling of the CNT, which was attributed solely to increased NCC activation.…”

Section: Discussionmentioning

confidence: 99%

Mutant Cullin 3 causes familial hyperkalemic hypertension via dominant effects

Ferdaus¹,

Miller²,

Agbor³

et al. 2017

JCI Insight

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Section: Discussionmentioning

confidence: 99%

Mutant Cullin 3 causes familial hyperkalemic hypertension via dominant effects

Ferdaus¹,

Miller²,

Agbor³

et al. 2017

JCI Insight

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“…Such increased SPAK/OSR1 phosphorylation potentially could be responsible, at least in part, for increased NCC and NKCC2 phosphorylation seen in the setting of acute salt loading. The current study found that, after acute salt loading, NOS3 KO mice had higher phosphorylation of NCC at threonine‐53; this is a key NCC regulatory site and is known to be phosphorylated by SPAK/OSR1 29, 30. In addition, a preliminary study has found that knockout of WNK4 (which phosphorylates SPAK) reduces total and phosphorylated NCC 31.…”

Section: Discussionmentioning

confidence: 55%

Nephron‐Specific Disruption of Nitric Oxide Synthase 3 Causes Hypertension and Impaired Salt Excretion

Gao

Stuart

Takahishi

et al. 2018

JAHA

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BackgroundIn vitro studies suggest that nephron nitric oxide synthase 3 (NOS3) modulates tubule Na+ transport.Methods and ResultsTo assess nephron NOS3 relevance in vivo, knockout (KO) mice with doxycycline‐inducible nephron‐wide deletion of NOS3 were generated. During 1 week of salt loading, KO mice, as compared with controls, had higher arterial pressure and Na+ retention, a tendency towards reduced plasma renin concentration, and unchanged glomerular filtration rate. Chronic high salt‐treated KO mice had modestly decreased total NCC and total SPAK/OSR1 versus controls, however percent phosphorylation of NCC (at T53) and of SPAK/OSR1 was increased. In contrast, total and phosphorylated NKCC2 (at T96/101) were suppressed by 50% each in KO versus control mice after chronic salt intake. In response to an acute salt load, KO mice had delayed urinary Na+ excretion versus controls; this delay was completely abolished by furosemide, partially reduced by hydrochlorothiazide, but not affected by amiloride. After 4 hours of an acute salt load, phosphorylated and total NCC were elevated in KO versus control mice. Acute salt loading did not alter total NKCC2 or SPAK/OSR1 in KO versus control mice but increased the percent phosphorylation of NKCC2 (at T96/101 and S126) and SPAK/OSR1 in KO versus control mice.ConclusionsThese findings indicate that nephron NOS3 is involved in blood pressure regulation and urinary Na+ excretion during high salt intake. Nephron NOS3 appears to regulate NKCC2 and NCC primarily during acute salt loading. These effects of NOS3 may involve SPAK/OSR1 as well as other pathways.

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“…Many aspects of the regulation of this pathway, including responses to dietary manipulation and hormonal signaling, have been delineated (40), but many questions remain. The precise mechanism by which CUL3 mutations lead to WNK kinase accumulation is still unknown, and the roles of other CUL3 adaptors, including KLHL2, are unknown.…”

Section: Discussionmentioning

confidence: 99%

The CUL3/KLHL3-WNK-SPAK/OSR1 pathway as a target for antihypertensive therapy

Ferdaus

McCormick

2016

American Journal of Physiology-Renal Physiology

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Chronic high blood pressure (hypertension) is the most common disease in the Unites States. While several classes of drugs exist to treat it, many patients (up to 10 million Americans) respond poorly to therapy, even when multiple classes are used. Recent evidence suggests that a significant portion of patients will always remain hypertensive despite maximum therapy with the drugs currently available. Therefore, there is a pressing need to develop novel antihypertensive agents. One limitation has been the identification of new targets, a limitation that has been overcome by recent insights into the mechanisms underlying monogenic forms of hypertension. The disease familial hyperkalemic hypertension is caused by mutations in with-no-lysine (WNK) kinases 1 and 4 and in cullin-3 and kelch-like 3, components of an E3 ubiquitin ligase complex that promotes WNK kinase degradation. The study of the mechanisms by which this pathway regulates blood pressure has identified several candidates for the development of new antihypertensive agents. This pathway is particularly attractive since its inhibition may not only reduce renal sodium reabsorption along multiple segments but may also reduce vascular tone. Here, we will describe the mechanisms by which this pathway regulate blood pressure and discuss the potential of targeting it to develop new antihypertensive drugs.

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Distal Convoluted Tubule

Cited by 72 publications

References 575 publications

Mutant Cullin 3 causes familial hyperkalemic hypertension via dominant effects

Mutant Cullin 3 causes familial hyperkalemic hypertension via dominant effects

Nephron‐Specific Disruption of Nitric Oxide Synthase 3 Causes Hypertension and Impaired Salt Excretion

The CUL3/KLHL3-WNK-SPAK/OSR1 pathway as a target for antihypertensive therapy

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