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  • 1
    Online Resource
    Online Resource
    mTORC2 critically regulates renal potassium handling
    American Society for Clinical Investigation ; 2016
    In:  Journal of Clinical Investigation Vol. 126, No. 5 ( 2016-4-4), p. 1773-1782
    Details
    In: Journal of Clinical Investigation, American Society for Clinical Investigation, Vol. 126, No. 5 ( 2016-4-4), p. 1773-1782
    Type of Medium: Online Resource
    ISSN: 0021-9738 , 1558-8238
    URL: Article
    URL: Article
    DOI: 10.1172/JCI80304
    DOI: 10.1172/JCI80304DS1
    Language: English
    Publisher: American Society for Clinical Investigation
    Publication Date: 2016
    detail.hit.zdb_id: 2018375-6
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  • 2
    Online Resource
    Online Resource
    The early part of the aldosterone sensitive distal nephron is the primary site of increased sodium absorption in a mouse model for Liddle’s syndrome (892.25)
    Wiley ; 2014
    In:  The FASEB Journal Vol. 28, No. S1 ( 2014-04)
    Details
    In: The FASEB Journal, Wiley, Vol. 28, No. S1 ( 2014-04)
    Type of Medium: Online Resource
    ISSN: 0892-6638 , 1530-6860
    URL: Issue
    URL: Article
    DOI: 10.1096/fsb2.v28.S1
    DOI: 10.1096/fasebj.28.1_supplement.892.25
    Language: English
    Publisher: Wiley
    Publication Date: 2014
    detail.hit.zdb_id: 1468876-1
    SSG: 12
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  • 3
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    Online Resource
    Critical role of the mineralocorticoid receptor in aldosterone-dependent and aldosterone-independent regulation of ENaC in the distal nephron
    American Physiological Society ; 2021
    In:  American Journal of Physiology-Renal Physiology Vol. 321, No. 3 ( 2021-09-01), p. F257-F268
    Details
    In: American Journal of Physiology-Renal Physiology, American Physiological Society, Vol. 321, No. 3 ( 2021-09-01), p. F257-F268
    Abstract: The epithelial Na + channel (ENaC) constitutes the rate-limiting step for Na + absorption in the aldosterone-sensitive distal nephron (ASDN) comprising the late distal convoluted tubule (DCT2), connecting tubule (CNT), and collecting duct (CD). 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/initial cortical CD (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 early part of the 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 [MR knockout (KO)] mice. Whole cell ENaC currents were investigated in isolated nephron fragments from the DCT2/CNT or CNT/CCD transition zones using the patch-clamp technique. ENaC activity was detectable in the 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 the DCT2/CNT were greatly reduced in MR KO mice compared with ENaC currents in the DCT2/CNT of control mice. Immunofluorescence for 11β-HSD2 was abundant in the CCD, less prominent in the CNT, and very low in the DCT2. We conclude that MR is critically important for maintaining aldosterone-independent ENaC activity in the DCT2/CNT. Aldosterone-independent MR activation is probably mediated by glucocorticoids due to low expression of 11β-HSD2. NEW & NOTEWORTHY Using a mouse model with inducible nephron-specific mineralocorticoid receptor (MR) deficiency, we demonstrated that MR is not only critical for maintaining aldosterone-dependent ENaC activity in CNT/CCD but also for aldosterone-independent ENaC activity in DCT2/CNT. Furthermore, we demonstrated that cells of this latter nephron segment express little 11β-HSD2, which probably allows glucocorticoids to stimulate MR, resulting in aldosterone-independent ENaC activity in DCT2/CNT. This site-specific ENaC regulation has physiologically relevant implications for renal sodium and potassium homeostasis.
    Type of Medium: Online Resource
    ISSN: 1931-857X , 1522-1466
    URL: Article
    DOI: 10.1152/ajprenal.00139.2021
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2021
    detail.hit.zdb_id: 1477287-5
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  • 4
    Online Resource
    Online Resource
    Aldosterone-dependent and -independent regulation of the epithelial sodium channel (ENaC) in mouse distal nephron
    American Physiological Society ; 2012
    In:  American Journal of Physiology-Renal Physiology Vol. 303, No. 9 ( 2012-11-01), p. F1289-F1299
    Details
    In: American Journal of Physiology-Renal Physiology, American Physiological Society, Vol. 303, No. 9 ( 2012-11-01), p. F1289-F1299
    Abstract: Aldosterone is thought to be the main hormone to stimulate the epithelial sodium channel (ENaC) in the aldosterone-sensitive distal nephron (ASDN) comprising the late distal convoluted tubule (DCT2), the connecting tubule (CNT) and the entire collecting duct (CD). There is immunohistochemical evidence for an axial gradient of ENaC expression along the ASDN with highest expression in the DCT2 and CNT. However, most of our knowledge about renal ENaC function stems from studies in the cortical collecting duct (CCD). Here we investigated ENaC function in the transition zone of DCT2/CNT or CNT/CCD microdissected from mice maintained on different sodium diets to vary plasma aldosterone levels. Single-channel recordings demonstrated amiloride-sensitive Na + channels in DCT2/CNT with biophysical properties typical for ENaC previously described in CNT/CCD. In animals maintained on a standard salt diet, the average ENaC-mediated whole cell current (Δ I ami ) was higher in DCT2/CNT than in CNT/CCD. A low salt diet increased Δ I ami in CNT/CCD but had little effect on Δ I ami in DCT2/CNT. To investigate whether aldosterone is necessary for ENaC activity in the DCT2/CNT, we used aldosterone synthase knockout (AS −/− ) mice that lack aldosterone. In CNT/CCD of AS −/− mice, Δ I ami was lower than that in wild-type (WT) animals and was not stimulated by a low salt diet. In contrast, in DCT2/CNT of AS −/− mice, Δ I ami was similar to that in DCT2/CNT of WT animals both on a standard and on a low salt diet. We conclude that ENaC function in the DCT2/CNT is largely independent of aldosterone which is in contrast to its known aldosterone sensitivity in CNT/CCD.
    Type of Medium: Online Resource
    ISSN: 1931-857X , 1522-1466
    URL: Article
    DOI: 10.1152/ajprenal.00247.2012
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2012
    detail.hit.zdb_id: 1477287-5
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  • 5
    Online Resource
    Online Resource
    Trypsin can activate the epithelial sodium channel (ENaC) in microdissected mouse distal nephron
    American Physiological Society ; 2008
    In:  American Journal of Physiology-Renal Physiology Vol. 295, No. 4 ( 2008-10), p. F1052-F1062
    Details
    In: American Journal of Physiology-Renal Physiology, American Physiological Society, Vol. 295, No. 4 ( 2008-10), p. F1052-F1062
    Abstract: Proteases are involved in the processing and activation of the epithelial sodium channel (ENaC). The aim of the present study was to investigate whether the prototypical serine protease trypsin can activate ENaC in microdissected, split-open mouse renal distal tubules. Whole-cell patch-clamp recordings from principal cells of connecting tubules (CNT) or cortical collecting ducts (CCD) demonstrated that addition of trypsin (20 μg/ml) to the bath solution increased the ENaC-mediated amiloride-sensitive whole cell current (Δ I Ami ) in the majority of cells. In contrast, trypsin applied in the presence of an excess of soybean trypsin inhibitor had no stimulatory effect. The Δ I Ami response to trypsin was variable, ranging from no apparent effect to a twofold increase in Δ I Ami with an average stimulatory effect of 31 or 37% in mice on low-Na + or standard Na + diet, respectively. In cultured M-1 mouse collecting duct cells, a robust stimulatory effect of trypsin on Δ I Ami was only observed in cells pretreated with protease inhibitors. This suggests that endogenous proteases contribute to ENaC activation in renal tubular cells and that the degree of ENaC prestimulation by endogenous proteases determines the magnitude of the stimulatory response to exogenous trypsin. In conclusion, we provide electrophysiological evidence that trypsin can stimulate ENaC activity in native renal mouse tubules. Thus, in the kidney, ENaC stimulation by extracellular proteases may be a relevant regulatory mechanism in vivo.
    Type of Medium: Online Resource
    ISSN: 1931-857X , 1522-1466
    URL: Article
    DOI: 10.1152/ajprenal.00031.2008
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2008
    detail.hit.zdb_id: 1477287-5
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  • 6
    Online Resource
    Online Resource
    High baseline ROMK activity in the mouse late distal convoluted and early connecting tubule probably contributes to aldosterone-independent K + secretion
    American Physiological Society ; 2022
    In:  American Journal of Physiology-Renal Physiology Vol. 322, No. 1 ( 2022-01-01), p. F42-F54
    Details
    In: American Journal of Physiology-Renal Physiology, American Physiological Society, Vol. 322, No. 1 ( 2022-01-01), p. F42-F54
    Abstract: The renal outer medullary K + channel (ROMK) is colocalized with the epithelial Na + channel (ENaC) in the late distal convoluted tubule (DCT2), connecting tubule (CNT), and cortical collecting duct (CCD). ENaC-mediated Na + absorption generates the electrical driving force for ROMK-mediated tubular K + secretion, which is critically important for maintaining renal K + homeostasis. ENaC activity is aldosterone dependent in the late CNT and early CCD (CNT/CCD) but aldosterone independent in the DCT2 and early CNT (DCT2/CNT). This suggests that under baseline conditions with low plasma aldosterone, ROMK-mediated K + secretion mainly occurs in the DCT2/CNT. Therefore, we hypothesized that baseline ROMK activity is higher in the DCT2/CNT than in the CNT/CCD. To test this hypothesis, patch-clamp experiments were performed in the DCT2/CNT and CNT/CCD microdissected from mice maintained on a standard diet. In single-channel recordings from outside-out patches, we detected typical ROMK channel activity in both the DCT2/CNT and CNT/CCD and confirmed that ROMK is the predominant K + channel in the apical membrane. Amiloride-sensitive and tertiapin-sensitive whole-cell currents were determined to assess ENaC and ROMK activity, respectively. As expected, baseline amiloride-sensitive current was high in the DCT2/CNT (∼370 pA) but low in the CNT/CCD (∼60 pA). Importantly, tertiapin-sensitive current was significantly higher in the DCT2/CNT than in the CNT/CCD (∼810 vs. ∼350 pA). We conclude that high ROMK activity in the DCT2/CNT is critical for aldosterone-independent renal K + secretion under baseline conditions. A low-K + diet significantly reduced ENaC but not ROMK activity in the DCT2/CNT. This suggests that modifying ENaC activity in the DCT2/CNT plays a key regulatory role in adjusting renal K + excretion to dietary K + intake. NEW & NOTEWORTHY ROMK-mediated renal K + secretion is essential for maintaining K + balance and requires a lumen negative transepithelial potential critically dependent on ENaC activity. Using microdissected distal mouse tubules, we demonstrated that baseline apical ROMK activity is high in the DCT2/CNT. Aldosterone-independent baseline ENaC activity is also high in the DCT2/CNT and downregulated by a low-K + diet, which highlights the important role of the DCT2/CNT in regulating K + secretion in an aldosterone-independent manner.
    Type of Medium: Online Resource
    ISSN: 1931-857X , 1522-1466
    URL: Article
    DOI: 10.1152/ajprenal.00252.2021
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2022
    detail.hit.zdb_id: 1477287-5
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  • 7
    Online Resource
    Online Resource
    In Liddle Syndrome, Epithelial Sodium Channel Is Hyperactive Mainly in the Early Part of the Aldosterone-Sensitive Distal Nephron
    Ovid Technologies (Wolters Kluwer Health) ; 2016
    In:  Hypertension Vol. 67, No. 6 ( 2016-06), p. 1256-1262
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 67, No. 6 ( 2016-06), p. 1256-1262
    Abstract: The epithelial sodium channel (ENaC) is rate limiting for Na + absorption in the aldosterone-sensitive distal nephron comprising the late distal convoluted tubule (DCT2), the connecting tubule (CNT), and the entire collecting duct. Liddle syndrome (pseudohyperaldosteronism), a severe form of salt-sensitive hypertension, is caused by gain-of-function mutations of ENaC, but the precise tubular site of increased ENaC function is unknown. In the cortical collecting duct (CCD), ENaC is known to be regulated by aldosterone. In contrast, we recently reported aldosterone-independent ENaC regulation in the early part of the aldosterone-sensitive distal nephron. Here, we investigated ENaC function in the transition zone of DCT2/CNT or CNT/CCD microdissected from mice homozygous for Liddle syndrome mutation or from wild-type control mice. Whole-cell patch-clamp recordings were used to measure amiloride-sensitive ENaC currents in nephron fragments from mice maintained on different sodium diets to vary plasma aldosterone levels. Our data indicate that in mice with Liddle syndrome, the primary site of increased Na + reabsorption is the DCT2/CNT. In addition, increased aldosterone responsiveness of ENaC in CNT/CCD may contribute to salt-sensitive hypertension in Liddle syndrome. Single channel properties of ENaC were similar in Liddle syndrome mutation and wild-type mice, but ENaC expression at the apical membrane was increased in Liddle syndrome mutation when compared with wild-type mice, in particular, in animals maintained on a high salt diet. Our findings highlight the importance of ENaC function and regulation in the early part of the aldosterone-sensitive distal nephron for the maintenance of sodium balance and blood pressure control.
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/HYPERTENSIONAHA.115.07061
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2016
    detail.hit.zdb_id: 2094210-2
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