Effects of FGF23 in the distal nephron

The localization of calbindin in the kidney and cerebellum of Hystrix cristata was investigated immunohistochemically using an antiserum against the 28k Da calbindin of chicken duodenum. Calbindin-D28k is an intracellular protein with a high affinity for calcium. This protein is exclusively localized in the distal convoluted tubules of the kidney and in Purkinje cells of the cerebellum. Functionaly, calbindin-D28k is supposed to be involved in the regulation of the reabsorption of calcium in the distal nephron, though the exact regulatory mechanisms are not yet known.

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With-No-Lysine Kinase 1 (WNK1) Augments TRPV4 Function in the Aldosterone-Sensitive Distal Nephron

Cells ◽

10.3390/cells10061482 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1482

Author(s):

Viktor N. Tomilin ◽

Kyrylo Pyrshev ◽

Naghmeh Hassanzadeh Khayyat ◽

Oleg Zaika ◽

Oleh Pochynyuk

Keyword(s):

Collecting Duct ◽

Chinese Hamster ◽

Dominant Negative ◽

K Channel ◽

Apical Plasma Membrane ◽

Dependent Manner ◽

Distal Nephron ◽

Potassium Homeostasis ◽

Wnk Kinases ◽

K Secretion

Kidneys play a central role in regulation of potassium homeostasis and maintenance of plasma K+ levels within a narrow physiological range. With-no-lysine (WNK) kinases, specifically WNK1 and WNK4, have been recognized to regulate K+ balance, in part, by orchestrating maxi K+ channel (BK)-dependent K+ secretion in the aldosterone-sensitive distal nephron (ASDN), which includes the connecting tubule and collecting duct. We recently demonstrated that the Ca2+-permeable TRPV4 channel is essential for BK activation in the ASDN. Furthermore, high K+ diet increases TRPV4 activity and expression largely in an aldosterone-dependent manner. In the current study, we aimed to test whether WNK kinases contribute to regulation of TRPV4 activity and its stimulation by aldosterone. Systemic inhibition of WNK with WNK463 (1 mg/kgBW for 3 days) markedly decreased TRPV4-dependent Ca2+ influx in freshly isolated split-opened collecting ducts. Aldosterone greatly increased TRPV4 activity and expression in cultured mpkCCDc14 cells and this effect was abolished in the presence of WNK463. Selective inhibition of WNK1 with WNK-in-11 (400 nM, 24 h) recapitulated the effects of WNK463 on TRPV4-dependent Ca2+ influx. Interestingly, WNK-in-11 did not interfere with up-regulation of TRPV4 expression by aldosterone, but prevented translocation of the channel to the apical plasma membrane. Furthermore, co-expression of TRPV4 and WNK1 into Chinese hamster ovary (CHO) cells increased the macroscopic TRPV4-dependent cation currents. In contrast, over-expression of TRPV4 with a dominant negative WNK1 variant (K233M) decreased the whole-cell currents, suggesting both stimulatory and permissive roles of WNK1 in regulation of TRPV4 activity. Overall, we show that WNK1 is essential for setting functional TRPV4 expression in the ASDN at the baseline and in response to aldosterone. We propose that this new mechanism contributes to regulation of K+ secretion and, by extension, urinary K+ levels to maintain systemic potassium homeostasis.

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Short-term nonpressor angiotensin II infusion stimulates sodium transporters in proximal tubule and distal nephron

Physiological Reports ◽

10.14814/phy2.12496 ◽

2015 ◽

Vol 3 (9) ◽

pp. e12496 ◽

Cited By ~ 21

Author(s):

Mien T. X. Nguyen ◽

Jiyang Han ◽

Donna L. Ralph ◽

Luciana C. Veiras ◽

Alicia A. McDonough

Keyword(s):

Angiotensin Ii ◽

Proximal Tubule ◽

Distal Nephron ◽

Short Term ◽

Sodium Transporters

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Genetic dissection of sodium and potassium transport along the aldosterone-sensitive distal nephron: Importance in the control of blood pressure and hypertension

FEBS Letters ◽

10.1016/j.febslet.2013.05.013 ◽

2013 ◽

Vol 587 (13) ◽

pp. 1929-1941 ◽

Cited By ~ 44

Author(s):

Bernard C. Rossier ◽

Olivier Staub ◽

Edith Hummler

Keyword(s):

Blood Pressure ◽

Potassium Transport ◽

Genetic Dissection ◽

Distal Nephron ◽

Sodium And Potassium

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The ClC-K2 Chloride Channel Is Critical for Salt Handling in the Distal Nephron

Journal of the American Society of Nephrology ◽

10.1681/asn.2016010085 ◽

2016 ◽

Vol 28 (1) ◽

pp. 209-217 ◽

Cited By ~ 50

Author(s):

J. Christopher Hennings ◽

Olga Andrini ◽

Nicolas Picard ◽

Marc Paulais ◽

Antje K. Huebner ◽

...

Keyword(s):

Chloride Channel ◽

Distal Nephron

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Effects of sodium intake on steady-state potassium excretion

AJP Renal Physiology ◽

10.1152/ajprenal.1984.246.6.f772 ◽

1984 ◽

Vol 246 (6) ◽

pp. F772-F778 ◽

Cited By ~ 1

Author(s):

D. B. Young ◽

T. E. Jackson ◽

U. Tipayamontri ◽

R. C. Scott

Keyword(s):

Steady State ◽

Potassium Concentration ◽

Sodium Intake ◽

Plasma Potassium ◽

Potassium Excretion ◽

Distal Nephron ◽

Concentration Data ◽

Potassium Intake ◽

Independent Variable ◽

The Relationship

The effects of changes in sodium intake on the steady-state relationship between plasma potassium concentration and potassium excretion were studied in 15 chronically adrenalectomized dogs. Throughout the experiments the dogs received aldosterone at a rate of 50 micrograms/day and methylprednisolone at 1 mg/day. The relationship between plasma potassium and steady-state potassium excretion was obtained by changing potassium intake from 10 to 30 to 100 meq/day, each level being maintained for 7-10 days. At the conclusion of each period at a given level of potassium intake, plasma potassium and excretion were measured and plotted, plasma potassium being the independent variable. Such a relationship was obtained while the dogs were on three different levels of sodium intake: 10, 100, and 200 meq/day. The curves from the data obtained at 100 and 200 meq/day sodium intake both were shifted to the left of the curve obtained at 10 meq/day (P less than 0.05), although the 100 and 200 meq/day curves were not different from each other. On the basis of these data one could predict that, at a plasma potassium concentration of 4.0 meq/liter, the animals would excrete potassium at a rate of 17 meq/day on a 10 meq/day sodium intake, 37 meq/day on a 100 meq/day sodium intake, and 47 meq/day on a 200 meq/day sodium intake. Urine flow and electrolyte concentration data are consistent with the hypothesis that the sodium intake effect on potassium excretion was mediated through increases in distal nephron flow rate and decreases in distal nephron potassium concentration.

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Corticosteroid regulation of amiloride-sensitive sodium-channel subunit mRNA expression in mouse kidney

Journal of Endocrinology ◽

10.1677/joe.0.1650025 ◽

2000 ◽

Vol 165 (1) ◽

pp. 25-37 ◽

Cited By ~ 28

Author(s):

P MacDonald ◽

S MacKenzie ◽

LE Ramage ◽

RW Brown ◽

Keyword(s):

Blood Pressure ◽

Sodium Channel ◽

Mrna Expression ◽

Collecting Duct ◽

In Situ Hybridisation ◽

Electrolyte Balance ◽

Distal Nephron ◽

Outer Medulla ◽

Subunit Mrna ◽

Sodium Handling

Corticosteroid control of distal nephron sodium handling, particularly through the amiloride-sensitive sodium channel (ENaC), has a key role in blood pressure regulation. The mechanisms regulating ENaC activity remain unclear. Despite the generation of useful mouse models of disorders of electrolyte balance and blood pressure, there has been little study of distal nephron sodium handling in this species. To investigate how corticosteroids regulate ENaC activity we isolated cDNA for the three mouse ENaC subunits (alpha, beta and gamma), enabling their quantitation by competitive PCR and in situ hybridisation. Kidneys were analysed from mice 6 days after adrenalectomy or placement of osmotic mini-pumps delivering aldosterone (50 microg/kg per day), dexamethasone (100 microg/kg per day), spironolactone (20 mg/kg per day) or vehicle alone (controls). In controls, renal ENaCalpha mRNA exceeded beta or gamma by approximately 1.75- to 2.8-fold. All subunit mRNAs were expressed in renal cortex and outer medulla, where the pattern of expression was fully consistent with localisation in collecting duct, whereas the distribution in cortex suggested expression extended beyond the collecting duct into adjacent distal tubule. Subunit mRNA expression decreased from cortex to outer medulla, with a gradual reduction in beta and gamma, and ENaCalpha decreased sharply ( approximately 50%) across the outer medulla. Expression of ENaCbeta and gamma (but not alpha) extended into inner medulla, suggesting the potential for inner medulla collecting duct cation channels in which at least ENaCbetagamma participate. Aldosterone significantly increased ENaC subunit expression; the other treatments had little effect. Aldosterone caused a 1.9- to 3.5-fold increase in ENaCalpha (particularly marked in outer medullary collecting duct), but changes for beta and gamma were minor and limited to the cortex. The results raise the possibility that medullary ENaCalpha upregulation by aldosterone will create more favourable subunit stoichiometry leading to a more substantial increase in ENaC activity. In cortex, such a mechanism is unlikely to have a major role.

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Effects of prostaglandin E2 on amiloride-blockable Na+ channels in a distal nephron cell line (A6)

AJP Cell Physiology ◽

10.1152/ajpcell.1994.267.5.c1414 ◽

1994 ◽

Vol 267 (5) ◽

pp. C1414-C1425 ◽

Cited By ~ 16

Author(s):

K. E. Kokko ◽

P. S. Matsumoto ◽

B. N. Ling ◽

D. C. Eaton

Keyword(s):

Prostaglandin E2 ◽

Apical Cell ◽

Na Channel ◽

Na Channels ◽

Channel Activity ◽

Distal Nephron ◽

Open Probability ◽

A6 Cells ◽

Channel Inhibition ◽

Camp Levels

We studied the mechanisms by which prostaglandin E2 (PGE2) regulates amiloride-blockable 4-pS Na+ channels in A6 distal nephron cells. With each apical cell-attached patch acting as its own control, acute (3-6 min) basolateral, but not apical, exposure to 1 microM PGE2 inhibited Na+ channel activity by decreasing the open probability (Po). This PGE2-induced inhibition was attenuated by 30 min pretreatment with the protein kinase C (PKC) antagonists 1 microM staurosporine or 100 microM D-sphingosine but was insensitive to pertussis toxin (PTX). Furthermore, the time course for channel inhibition by acute PGE2 correlated with a transient increase in intracellular inositol 1,4,5-trisphosphate (IP3) levels. In contrast, after chronic (10-50 min) exposure of A6 cells to 1 microM basolateral PGE2, channel activity was stimulated compared with controls. This stimulation was due to an increase in the number of apical Na+ channels, similar to the effect of maneuvers that increase intracellular adenosine 3',5'-cyclic monophosphate (cAMP) levels in A6 cells (22). Indeed, chronic exposure to basolateral PGE2 correlated with a sustained increase in cAMP levels. In conclusion, 1) the regulation of apical 4-pS highly selective Na+ channel activity by basolateral PGE2 is a complicated biphasic process, which includes inhibition by acute PGE2 and stimulation by chronic PGE2 exposure; 2) acute PGE2 promotes a transient generation of IP3 which activates Ca(2+)-dependent PKC and promotes a decrease in Po; 3) chronic PGE2 promotes a sustained generation of cAMP that leads to an increase in channel density; and 4) both the acute and chronic effects of PGE2 on Na+ channels are PTX-insensitive processes.

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Low Na intake suppresses expression of CYP2C23 and arachidonic acid-induced inhibition of ENaC

AJP Renal Physiology ◽

10.1152/ajprenal.00112.2006 ◽

2006 ◽

Vol 291 (6) ◽

pp. F1192-F1200 ◽

Cited By ~ 25

Author(s):

Peng Sun ◽

Dao-Hong Lin ◽

Tong Wang ◽

Elisa Babilonia ◽

Zhijian Wang ◽

...

Keyword(s):

Arachidonic Acid ◽

Collecting Duct ◽

Inhibitory Effect ◽

Thick Ascending Limb ◽

Epoxyeicosatrienoic Acid ◽

Distal Nephron ◽

Na Transport ◽

Deficient Diet ◽

Epithelial Na Channels ◽

Clamp Study

We previously demonstrated that arachidonic acid (AA) inhibits epithelial Na channels (ENaC) through the cytochrome P-450 (CYP) epoxygenase-dependent pathway ( 34 ). In the present study, we tested the hypothesis that low Na intake suppresses the expression of CYP2C23, which is mainly responsible for converting AA to epoxyeicosatrienoic acid (EET) in the kidney ( 11 ) and attenuates the AA-induced inhibition of ENaC. Immunostaining showed that CYP2C23 is expressed in the Tamm-Horsfall protein (THP)-positive and aquaporin 2 (AQP2)-positive tubules. This suggests that CYP2C23 is expressed in the thick ascending limb (TAL) and collecting duct (CD). Na restriction significantly suppressed the expression of CYP2C23 in the TAL and CD. Western blot also demonstrated that the expression of CYP2C23 in renal cortex and outer medulla diminished in rats on Na-deficient diet (Na-D) but increased in those on high-Na diet (4%). Moreover, the content of 11,12-epoxyeicosatrienoic acid (EET) decreased in the isolated cortical CD from rats on Na-D compared with those on a normal-Na diet (0.5%). Patch-clamp study showed that application of 15 μM AA inhibited the activity of ENaC by 77% in the CCD of rats on a Na-D for 3 days. However, the inhibitory effect of AA on ENaC was significantly attenuated in rats on Na-D for 14 days. Furthermore, inhibition of CYP epoxygenase with MS-PPOH increased the ENaC activity in the CCD of rats on a control Na diet. We also used microperfusion technique to examine the effect of MS-PPOH on Na transport in the distal nephron. Application of MS-PPOH significantly increased Na absorption in the distal nephron of control rats but had no significant effect on Na absorption in rats on Na-D for 14 days. We conclude that low Na intake downregulates the activity and expression of CYP2C23 and attenuates the inhibitory effect of AA on Na transport.

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