scholarly journals Effect of Angiotensin II on ENaC in the Distal Convoluted Tubule and in the Cortical Collecting Duct of Mineralocorticoid Receptor Deficient Mice

2020 ◽  
Vol 9 (7) ◽  
Author(s):  
Peng Wu ◽  
Zhong‐Xiuzi Gao ◽  
Dan‐Dan Zhang ◽  
Xin‐Peng Duan ◽  
Andrew S. Terker ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Mineralocorticoid Receptor ◽  
Sodium Intake ◽  
Collecting Duct ◽  
Distal Convoluted Tubule ◽  
Cortical Collecting Duct ◽  
Wild Type ◽  
Low Sodium ◽  
High K ◽  
Independent Mechanism

Background Angiotensin II stimulates epithelial Na + channel (ENaC) by aldosterone‐independent mechanism. We now test the effect of angiotensin II on ENaC in the distal convoluted tubule (DCT) and cortical collecting duct (CCD) of wild‐type (WT) and kidney‐specific mineralocorticoid receptor knockout mice (KS‐MR‐KO). Methods and Results We used electrophysiological, immunoblotting and renal‐clearance methods to examine the effect of angiotensin II on ENaC in KS‐MR‐KO and wild‐type mice. High K + intake stimulated ENaC in the late DCT/early connecting tubule (DCT2/CNT) and in the CCD whereas low sodium intake stimulated ENaC in the CCD but not in the DCT2/CNT. The deletion of MR abolished the stimulatory effect of high K + and low sodium intake on ENaC, partially inhibited ENaC in DCT2/CNT but almost abolished ENaC activity in the CCD. Application of losartan inhibited ENaC only in DCT2/CNT of both wild‐type and KS‐MR‐KO mice but not in the CCD. Angiotensin II infusion for 3 days has a larger stimulatory effect on ENaC in the DCT2/CNT than in the CCD. Three lines of evidence indicate that angiotensin II can stimulate ENaC by MR‐independent mechanism: (1) angiotensin II perfusion augmented ENaC expression in KS‐MR‐KO mice; (2) angiotensin II stimulated ENaC in the DCT2/CNT but to a lesser degree in the CCD in KS‐MR‐KO mice; (3) angiotensin II infusion augmented benzamil‐induced natriuresis, increased the renal K + excretion and corrected hyperkalemia of KS‐MR‐KO mice. Conclusions Angiotensin II‐induced stimulation of ENaC occurs mainly in the DCT2/CNT and to a lesser degree in the CCD and MR plays a dominant role in determining ENaC activity in the CCD but to a lesser degree in the DCT2/CNT.

scholarly journals Role of WNK4 and kidney-specific WNK1 in mediating the effect of high dietary K+ intake on ROMK channel in the distal convoluted tubule

2018 ◽  
Vol 315 (2) ◽  
pp. F223-F230 ◽  
Author(s):  
Peng Wu ◽  
Zhong-Xiuzi Gao ◽  
Xiao-Tong Su ◽  
David H. Ellison ◽  
Juliette Hadchouel ◽  
...  
Keyword(s):  
Renal Clearance ◽  
Collecting Duct ◽  
Distal Convoluted Tubule ◽  
Cortical Collecting Duct ◽  
Cell Models ◽  
High K ◽  
Cell Recording ◽  
Clearance Study ◽  
Stimulation Of

With-no-lysine kinase 4 (WNK4) and kidney-specific (KS)-WNK1 regulate ROMK (Kir1.1) channels in a variety of cell models. We now explore the role of WNK4 and KS-WNK1 in regulating ROMK in the native distal convoluted tubule (DCT)/connecting tubule (CNT) by measuring tertiapin-Q (TPNQ; ROMK inhibitor)-sensitive K+ currents with whole cell recording. TPNQ-sensitive K+ currents in DCT2/CNT of KS- WNK1−/− and WNK4−/− mice were significantly smaller than that of WT mice. In contrast, the basolateral K+ channels (a Kir4.1/5.1 heterotetramer) in the DCT were not inhibited. Moreover, WNK4−/− mice were hypokalemic, while KS- WNK1−/− mice had normal plasma K+ levels. High K+ (HK) intake significantly increased TPNQ-sensitive K+ currents in DCT2/CNT of WT and WNK4−/− mice but not in KS- WNK1−/− mice. However, TPNQ-sensitive K+ currents in the cortical collecting duct (CCD) were normal not only under control conditions but also significantly increased in response to HK in KS- WNK1−/− mice. This suggests that the deletion of KS-WNK1-induced inhibition of ROMK occurs only in the DCT2/CNT. Renal clearance study further demonstrated that the deletion of KS-WNK1 did not affect the renal ability of K+ excretion under control conditions and during increasing K+ intake. Also, HK intake did not cause hyperkalemia in KS- WNK1−/− mice. We conclude that KS-WNK1 but not WNK4 is required for HK intake-induced stimulation of ROMK activity in DCT2/CNT. However, KS-WNK1 is not essential for HK-induced stimulation of ROMK in the CCD, and the lack of KS-WNK1 does not affect net renal K+ excretion.

Angiotensin II increases chloride absorption in the cortical collecting duct in mice through a pendrin-dependent mechanism

2007 ◽  
Vol 292 (3) ◽  
pp. F914-F920 ◽  
Author(s):  
Vladimír Pech ◽  
Young Hee Kim ◽  
Alan M. Weinstein ◽  
Lorraine A. Everett ◽  
Truyen D. Pham ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Chloride Transport ◽  
Collecting Duct ◽  
Cortical Collecting Duct ◽  
Wild Type ◽  
Atpase Inhibitor ◽  
Chloride Absorption ◽  
Transepithelial Voltage ◽  
Dependent Mechanism

Pendrin ( Slc26a4) localizes to type B and non-A, non-B intercalated cells in the distal convoluted tubule, the connecting tubule, and the cortical collecting duct (CCD), where it mediates apical Cl−/HCO3− exchange. The purpose of this study was to determine whether angiotensin II increases transepithelial net chloride transport, JCl, in mouse CCD through a pendrin-dependent mechanism. JCl and transepithelial voltage, VT, were measured in CCDs perfused in vitro from wild-type and Slc26a4 null mice ingesting a NaCl-replete diet or a NaCl-replete diet and furosemide. In CCDs from wild-type mice ingesting a NaCl-replete diet, VT and JCl were not different from zero either in the presence or absence of angiotensin II (10−8 M) in the bath. Thus further experiments employed mice given the high-NaCl diet and furosemide to upregulate renal pendrin expression. CCDs from furosemide-treated wild-type mice had a lumen-negative VT and absorbed Cl−. With angiotensin II in the bath, Cl− absorption doubled although VT did not become more lumen negative. In contrast, in CCDs from furosemide-treated Slc26a4 null mice, Cl− secretion and a VT of ∼0 were observed, neither of which changed with angiotensin II application. Inhibiting ENaC with benzamil abolished VT although JCl fell only ∼50%. Thus substantial Cl− absorption is observed in the absence of an electromotive force. Attenuating apical anion exchange with the peritubular application of the H+-ATPase inhibitor bafilomycin abolished benzamil-insensitive Cl− absorption. In conclusion, angiotensin II increases transcellular Cl− absorption in the CCD through a pendrin- and H+-ATPase-dependent process.

scholarly journals Kidney-specific WNK1 regulates sodium reabsorption and potassium secretion in mouse cortical collecting duct

2013 ◽  
Vol 304 (4) ◽  
pp. F397-F402 ◽  
Author(s):  
Chih-Jen Cheng ◽  
Michel Baum ◽  
Chou-Long Huang
Keyword(s):  
Collecting Duct ◽  
Sodium Reabsorption ◽  
Thick Ascending Limb ◽  
Cortical Collecting Duct ◽  
Wild Type ◽  
High K ◽  
In The Wild ◽  
Potassium Secretion ◽  
And Control

Kidney-specific with-no-lysine kinase 1 (KS-WNK1) is a kinase-deficient variant of WNK1 that is expressed exclusively in the kidney. It is abundantly expressed in the distal convoluted tubule (DCT) and to a lesser extent in the cortical thick ascending limb (cTAL), connecting tubule, and cortical collecting duct (CCD). KS-WNK1 inhibits Na+-K+-2Cl−- and sodium chloride cotransporter-mediated Na+ reabsorption in cTAL and DCT, respectively. Here, we investigated the role of KS-WNK1 in regulating Na+ and K+ transport in CCD using in vitro microperfusion of tubules isolated from KS-WNK1 knockout mice and control wild-type littermates. Because baseline K+ secretion and Na+ reabsorption were negligible in mouse CCD, we studied tubules isolated from mice fed a high-K+ diet for 2 wk. Compared with that in wild-type tubules, K+ secretion was reduced in KS-WNK1 knockout CCD perfused at a low luminal fluid rate of ∼1.5 nl/min. Na+ reabsorption and the lumen-negative transepithelial potential difference were also lower in the KS-WNK1 knockout CCD compared with control CCD. Increasing the perfusion rate to ∼5.5 nl/min stimulated K+ secretion in the wild-type as well as knockout CCD. The magnitudes of flow-stimulated increase in K+ secretion were similar in wild-type and knockout CCD. Maxi-K+ channel inhibitor iberiotoxin had no effect on K+ secretion when tubules were perfused at ∼1.5 nl/min, but completely abrogated the flow-dependent increase in K+ secretion at ∼5.5 nl/min. These findings support the notion that KS-WNK1 stimulates ROMK-mediated K+ secretion, but not flow-dependent K+ secretion mediated by maxi-K+ channels in CCD. In addition, KS-WNK1 plays a role in regulating Na+ transport in the CCD.

scholarly journals SGK1-dependent ENaC processing and trafficking in mice with high dietary K intake and elevated aldosterone

2017 ◽  
Vol 312 (1) ◽  
pp. F65-F76 ◽  
Author(s):  
Lei Yang ◽  
Gustavo Frindt ◽  
Florian Lang ◽  
Dietmar Kuhl ◽  
Volker Vallon ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Collecting Duct ◽  
Surface Expression ◽  
Bk Channels ◽  
Na Channel ◽  
Cortical Collecting Duct ◽  
Wild Type ◽  
Altered Expression ◽  
Principal Cells ◽  
High K

We examined renal Na and K transporters in mice with deletions in the gene encoding the aldosterone-induced protein SGK1. The knockout mice were hyperkalemic, and had altered expression of the subunits of the epithelial Na channel (ENaC). The kidneys showed decreased expression of the cleaved forms of the γENaC subunit, and the fully glycosylated form of the βENaC subunits when animals were fed a high-K diet. Knockout animals treated with exogenous aldosterone also had reduced subunit processing and diminished surface expression of βENaC and γENaC. Expression of the three upstream Na transporters NHE3, NKCC2, and NCC was reduced in both wild-type and knockout mice in response to K loading. The activity of ENaC measured as whole cell amiloride-sensitive current ( INa) in principal cells of the cortical collecting duct (CCD) was minimal under control conditions but was increased by a high-K diet to a similar extent in knockout and wild-type animals. INa in the connecting tubule also increased similarly in the two genotypes in response to exogenous aldosterone administration. The activities of both ROMK channels in principal cells and BK channels in intercalated cells of the CCD were unaffected by the deletion of SGK1. Acute treatment of animals with amiloride produced similar increases in Na excretion and decreases in K excretion in the two genotypes. The absence of changes in ENaC activity suggests compensation for decreased surface expression. Altered K balance in animals lacking SGK1 may reflect defects in ENaC-independent K excretion.

scholarly journals Kidney-specific WNK1 inhibits sodium reabsorption in the cortical thick ascending limb

2012 ◽  
Vol 303 (5) ◽  
pp. F667-F673 ◽  
Author(s):  
Chih-Jen Cheng ◽  
Thao Truong ◽  
Michel Baum ◽  
Chou-Long Huang
Keyword(s):  
Collecting Duct ◽  
Urine Volume ◽  
Sodium Reabsorption ◽  
Renal Tubules ◽  
Thick Ascending Limb ◽  
Cortical Collecting Duct ◽  
Wild Type ◽  
High K

Kidney-specific WNK1 (KS-WNK1) is a variant of full-length WNK1. Previous studies have reported that KS-WNK1 is predominantly expressed in the distal convoluted tubule (DCT) where it regulates sodium-chloride cotransporter. The role of KS-WNK1 in other nephron segments is less clear. Here, we measured the expression of KS-WNK1 transcript in microdissected renal tubules and found that KS-WNK1 was most abundant in the DCT, followed by cortical thick ascending limb (cTAL), connecting tubule, and cortical collecting duct. A high K+ diet enhanced the expression of KS-WNK1 in the DCT and cTAL, selectively. It has been reported that a high-K diet suppresses Na+ reabsorption in TAL. To understand the role of KS-WNK1 in Na+ transport in cTAL and the regulation by dietary K+, we examined Na+ reabsorption using in vitro microperfusion in cTAL isolated from KS-WNK1-knockout mice and wild-type littermates fed either a control-K+ or high-K+ diet. Furosemide-sensitive Na+ reabsorption in cTAL was higher in KS-WNK1-knockout (KO) mice than in wild-type. A high-K+ diet inhibited Na+ reabsorption in cTAL from wild-type mice, but the inhibition was eliminated in KS-WNK1-KO mice. We further examined the role of KS-WNK1 using transgenic mice that overexpress KS-WNK1. Na+ reabsorption in cTAL was lower in transgenic than in wild-type mice. In whole animal clearance studies, a high-K+ diet increased daily urine volume and urinary Na+ and K+ excretion in wild-type mice, which was blunted in KS-WNK1-KO mice. Thus KS-WNK1 inhibits Na+ reabsorption in cTAL and mediates the inhibition of Na+ reabsorption in the segment by a high-K diet.

Increased Renal Sensitivity to Aldosterone in the Potassium-Loaded Rat

1976 ◽  
Vol 51 (s3) ◽  
pp. 315s-317s
Author(s):  
W. R. Adam ◽  
J. W. Funder
Keyword(s):  
Sodium Intake ◽  
Control Diet ◽  
High Potassium ◽  
High Sodium ◽  
Low Sodium Diet ◽  
Low Sodium ◽  
High K ◽  
And Control

1. The renal response to aldosterone (urinary sodium and potassium excretion) was determined in adrenalectomized rats previously fed either a high potassium diet or a control diet. High K+ rats showed an enhanced response to aldosterone at all doses tested. 2. This enhanced response to aldosterone required the presence of the adrenal glands during the induction period, could be suppressed by a high sodium intake, but could not be induced by a low sodium diet. 3. No difference between high K+ and control rats could be detected in renal mineralocorticoid receptors, assessed by both in vivo and in vitro binding of tritiated aldosterone. 4. The method of the induction, and the mechanism of the enhanced response, remain to be defined.

Critical role of the mineralocorticoid receptor in aldosterone-dependent and aldosterone-independent regulation of ENaC in the distal nephron

2021 ◽  
Author(s):  
Viatcheslav Nesterov ◽  
Marko Bertog ◽  
Jérémie Canonica ◽  
Edith Hummler ◽  
Richard Coleman ◽  
...  
Keyword(s):  
Mineralocorticoid Receptor ◽  
Collecting Duct ◽  
Critical Role ◽  
Sodium Absorption ◽  
Cortical Collecting Duct ◽  
Distal Nephron ◽  
Patch Clamp Technique ◽  
Transition Zones ◽  
Rate Limiting Step

The epithelial sodium channel (ENaC) constitutes the rate-limiting step for sodium absorption in the aldosterone-sensitive distal nephron (ASDN) comprising the late distal convoluted tubule (DCT2), the connecting tubule (CNT) and the collecting duct. Previously, we demonstrated that ENaC activity in the DCT2/CNT transition zone is constitutively high and independent of aldosterone, in contrast to its aldosterone dependence in the late CNT and initial cortical collecting duct (CNT/CCD). The mineralocorticoid receptor (MR) is expressed in the entire ASDN. Its activation by glucocorticoids is prevented through 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2) abundantly expressed in the late but probably not the early part of ASDN. We hypothesized that ENaC function in the early part of the ASDN is aldosterone-independent but may depend on MR activated by glucocorticoids due to low 11β-HSD2 abundance. To test this hypothesis, we used doxycycline-inducible nephron-specific MR-deficient mice (MR KO). Whole-cell ENaC currents were investigated in isolated nephron fragments from DCT2/CNT or CNT/CCD transition zones using the patch-clamp technique. ENaC activity was detectable in CNT/CCD of control mice but absent or barely detectable in the majority of CNT/CCD preparations from MR KO mice. Importantly, ENaC currents in DCT2/CNT were greatly reduced in MR KO mice compared to ENaC currents in DCT2/CNT of control mice. Immunofluorescence for 11β-HSD2 was abundant in CCD, less prominent in CNT and very low in DCT2. We conclude that MR is critically important for maintaining aldosterone-independent ENaC activity in DCT2/CNT. Aldosterone-independent MR activation is probably mediated by glucocorticoids due to low expression of 11β-HSD2.

scholarly journals Site-1 Protease-Derived Soluble (Pro)Renin Receptor Contributes to Angiotensin II–Induced Hypertension in Mice

Hypertension ◽  
2020 ◽  
Author(s):  
Ye Feng ◽  
Kexin Peng ◽  
Renfei Luo ◽  
Fei Wang ◽  
Tianxin Yang
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Collecting Duct ◽  
Short Circuit ◽  
Ussing Chamber ◽  
Short Circuit Current ◽  
Duct Cell ◽  
Ang Ii ◽  
Cortical Collecting Duct ◽  
Induced Hypertension

Activation of PRR ([pro]renin receptor) contributes to enhancement of intrarenal RAS and renal medullary α-ENaC and thus elevated blood pressure during Ang II (angiotensin II) infusion. The goal of the present study was to test whether such action of PRR was mediated by sPRR (soluble PRR), generated by S1P (site-1 protease), a newly identified PRR cleavage protease. F1 B6129SF1/J mice were infused for 6 days with control or Ang II at 300 ng/kg per day alone or in combination with S1P inhibitor PF-429242 (PF), and blood pressure was monitored by radiotelemetry. S1P inhibition significantly attenuated Ang II–induced hypertension accompanied with suppressed urinary and renal medullary renin levels and expression of renal medullary but not renal cortical α-ENaC expression. The effects of S1P inhibition were all reversed by supplement with histidine-tagged sPRR termed as sPRR-His. Ussing chamber technique was performed to determine amiloride-sensitive short-circuit current, an index of ENaC activity in confluent mouse cortical collecting duct cell line cells exposed for 24 hours to Ang II, Ang II + PF, or Ang II + PF + sPRR-His. Ang II–induced ENaC activity was blocked by PF, which was reversed by sPRR-His. Together, these results support that S1P-derived sPRR mediates Ang II–induced hypertension through enhancement of intrarenal renin level and activation of ENaC.

Stimulation of Cl- self exchange by intracellular HCO3- in rabbit cortical collecting duct

1989 ◽  
Vol 257 (1) ◽  
pp. C94-C101 ◽  
Author(s):  
K. Matsuzaki ◽  
J. B. Stokes ◽  
V. L. Schuster
Keyword(s):  
Anion Exchange ◽  
Intracellular Ph ◽  
Rate Coefficient ◽  
Collecting Duct ◽  
Cortical Collecting Duct ◽  
High K ◽  
Shift Experiment ◽  
Ethanesulfonic Acid ◽  
The Individual ◽  
Stimulation Of

In rabbit cortical collecting duct, Cl- self exchange accounts for most of the transepithelial Cl- tracer rate coefficient, KCl (nm/s); a small fraction is effected by Cl--HCO3- exchange and Cl- diffusion. We previously reported that changing from a CO2-free N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES) bath to a 5% CO2-25 mM HCO3- bath stimulates Cl- self exchange. Here, we examine in further detail the individual components of the CO2-HCO3- system that stimulate KCl. Addition of 0.5% CO2 to a HEPES bath (final pH = 7.24) stimulated KCl by 70 +/- 19 nm/s, a delta KCl comparable to that induced by 1% CO2 (pH 7.12), 6% CO2 (pH 6.6), or 6% CO2-25 mM HCO3- (pH 7.4). The roles of intracellular pH (pHi) and HCO3- concentration were examined by clamping pHi using high K+ and nigericin. Increasing pHi from 6.9 to 7.6 in solutions without exogenous CO2 or HCO3- increased KCl by 71 +/- 17 nm/s. These results suggest that pHi might regulate anion exchange. However, during such a pHi-shift experiment, metabolically derived CO2 produces a concomitant change in intracellular HCO3- concentration [( HCO3-]i). To determine whether an increase in [HCO3-]i could stimulate Cl- self exchange, we replaced HEPES with 6% CO2-5 mM HCO3- isohydrically (pHi clamped at 6.9). With this increase in [HCO3-]i at constant pHi, KCl increased by 51 +/- 10 nm/s. These maneuvers had negligible effects on Cl- diffusion and Cl--HCO3- exchange. These experiments demonstrate that increases in cell [HCO3-] (or perhaps CO2) can stimulate transepithelial anion exchange.(ABSTRACT TRUNCATED AT 250 WORDS)

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