Trimethoprim inhibits renal H+/K+ ATPase in states of K+ depletion

Niklas Ayasse; Peder Berg; Samuel L Svendsen; Amalie Quist Rousing; Mads Vaarby Sørensen; Natalya U Fedosova; Jens Leipziger

doi:10.1152/ajprenal.00273.2023

Trimethoprim inhibits renal H+/K+ ATPase in states of K+ depletion

Niklas Ayasse, Peder Berg, Samuel L Svendsen, Amalie Quist Rousing, Mads Vaarby Sørensen, Natalya U Fedosova, Jens Leipziger

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

1 Citationer (Scopus)

Abstract

There is growing consensus that under physiological conditions, collecting duct H+ secretion is independent of epithelial Na+ channel (ENaC) activity. We have recently shown that the direct ENaC inhibitor benzamil acutely impairs H+ excretion by blocking renal H+-K+-ATPase. However, the question remains whether inhibition of ENaC per se causes alterations in renal H+ excretion. To revisit this question, we studied the effect of the antibiotic trimethoprim (TMP), which is well known to cause K+ retention by direct ENaC inhibition. The acute effect of TMP (5 lg/g body wt) was assessed in bladder-catheterized mice, allowing real-time measurement of urinary pH, electrolyte, and acid excretion. Dietary K+ depletion was used to increase renal H+- K+-ATPase activity. In addition, the effect of TMP was investigated in vitro using pig gastric H+-K+-ATPase-enriched membrane vesicles. TMP acutely increased natriuresis and decreased kaliuresis, confirming its ENaC-inhibiting property. Under control diet conditions, TMP had no effect on urinary pH or acid excretion. Interestingly, K+ depletion unmasked an acute urine alkalizing effect of TMP. This finding was corroborated by in vitro experiments showing that TMP inhibits H+-K+-ATPase activity, albeit at much higher concentrations than benzamil. In conclusion, under control diet conditions, TMP inhibited ENaC function without changing urinary H+ excretion. This finding further supports the hypothesis that the inhibition of ENaC per se does not impair H+ excretion in the collecting duct. Moreover, TMP-induced urinary alkalization in animals fed a low-K+ diet highlights the importance of renal H+-K+-ATPase-mediated H+ secretion in states of K+ depletion.

Originalsprog	Engelsk
Tidsskrift	American journal of physiology. Renal physiology
Vol/bind	326
Nummer	1
Sider (fra-til)	F143-F151
ISSN	1931-857X
DOI	https://doi.org/10.1152/ajprenal.00273.2023
Status	Udgivet - 1 jan. 2024

Adgang til dokumentet

10.1152/ajprenal.00273.2023

Citationsformater

@article{60fcdc2d23274f03ad8f567b59054aad,

title = "Trimethoprim inhibits renal H+/K+ ATPase in states of K+ depletion",

abstract = "There is growing consensus that under physiological conditions, collecting duct H+ secretion is independent of epithelial Na+ channel (ENaC) activity. We have recently shown that the direct ENaC inhibitor benzamil acutely impairs H+ excretion by blocking renal H+-K+-ATPase. However, the question remains whether inhibition of ENaC per se causes alterations in renal H+ excretion. To revisit this question, we studied the effect of the antibiotic trimethoprim (TMP), which is well known to cause K+ retention by direct ENaC inhibition. The acute effect of TMP (5 lg/g body wt) was assessed in bladder-catheterized mice, allowing real-time measurement of urinary pH, electrolyte, and acid excretion. Dietary K+ depletion was used to increase renal H+- K+-ATPase activity. In addition, the effect of TMP was investigated in vitro using pig gastric H+-K+-ATPase-enriched membrane vesicles. TMP acutely increased natriuresis and decreased kaliuresis, confirming its ENaC-inhibiting property. Under control diet conditions, TMP had no effect on urinary pH or acid excretion. Interestingly, K+ depletion unmasked an acute urine alkalizing effect of TMP. This finding was corroborated by in vitro experiments showing that TMP inhibits H+-K+-ATPase activity, albeit at much higher concentrations than benzamil. In conclusion, under control diet conditions, TMP inhibited ENaC function without changing urinary H+ excretion. This finding further supports the hypothesis that the inhibition of ENaC per se does not impair H+ excretion in the collecting duct. Moreover, TMP-induced urinary alkalization in animals fed a low-K+ diet highlights the importance of renal H+-K+-ATPase-mediated H+ secretion in states of K+ depletion.",

keywords = "Acidosis/metabolism, Animals, Anti-Bacterial Agents/pharmacology, Epithelial Sodium Channels/metabolism, H(+)-K(+)-Exchanging ATPase/metabolism, Kidney Tubules, Collecting/metabolism, Mice, Sodium/metabolism, Swine, Trimethoprim/pharmacology, metabolic acidosis, sulfamethoxazole, benzamil, epithelial Na+ channel",

author = "Niklas Ayasse and Peder Berg and Svendsen, {Samuel L} and Rousing, {Amalie Quist} and S{\o}rensen, {Mads Vaarby} and Fedosova, {Natalya U} and Jens Leipziger",

year = "2024",

month = jan,

day = "1",

doi = "10.1152/ajprenal.00273.2023",

language = "English",

volume = "326",

pages = "F143--F151",

journal = "American journal of physiology. Renal physiology",

issn = "1931-857X",

publisher = "American Physiological Society",

number = "1",

}

TY - JOUR

T1 - Trimethoprim inhibits renal H+/K+ ATPase in states of K+ depletion

AU - Ayasse, Niklas

AU - Berg, Peder

AU - Svendsen, Samuel L

AU - Rousing, Amalie Quist

AU - Sørensen, Mads Vaarby

AU - Fedosova, Natalya U

AU - Leipziger, Jens

PY - 2024/1/1

Y1 - 2024/1/1

N2 - There is growing consensus that under physiological conditions, collecting duct H+ secretion is independent of epithelial Na+ channel (ENaC) activity. We have recently shown that the direct ENaC inhibitor benzamil acutely impairs H+ excretion by blocking renal H+-K+-ATPase. However, the question remains whether inhibition of ENaC per se causes alterations in renal H+ excretion. To revisit this question, we studied the effect of the antibiotic trimethoprim (TMP), which is well known to cause K+ retention by direct ENaC inhibition. The acute effect of TMP (5 lg/g body wt) was assessed in bladder-catheterized mice, allowing real-time measurement of urinary pH, electrolyte, and acid excretion. Dietary K+ depletion was used to increase renal H+- K+-ATPase activity. In addition, the effect of TMP was investigated in vitro using pig gastric H+-K+-ATPase-enriched membrane vesicles. TMP acutely increased natriuresis and decreased kaliuresis, confirming its ENaC-inhibiting property. Under control diet conditions, TMP had no effect on urinary pH or acid excretion. Interestingly, K+ depletion unmasked an acute urine alkalizing effect of TMP. This finding was corroborated by in vitro experiments showing that TMP inhibits H+-K+-ATPase activity, albeit at much higher concentrations than benzamil. In conclusion, under control diet conditions, TMP inhibited ENaC function without changing urinary H+ excretion. This finding further supports the hypothesis that the inhibition of ENaC per se does not impair H+ excretion in the collecting duct. Moreover, TMP-induced urinary alkalization in animals fed a low-K+ diet highlights the importance of renal H+-K+-ATPase-mediated H+ secretion in states of K+ depletion.

AB - There is growing consensus that under physiological conditions, collecting duct H+ secretion is independent of epithelial Na+ channel (ENaC) activity. We have recently shown that the direct ENaC inhibitor benzamil acutely impairs H+ excretion by blocking renal H+-K+-ATPase. However, the question remains whether inhibition of ENaC per se causes alterations in renal H+ excretion. To revisit this question, we studied the effect of the antibiotic trimethoprim (TMP), which is well known to cause K+ retention by direct ENaC inhibition. The acute effect of TMP (5 lg/g body wt) was assessed in bladder-catheterized mice, allowing real-time measurement of urinary pH, electrolyte, and acid excretion. Dietary K+ depletion was used to increase renal H+- K+-ATPase activity. In addition, the effect of TMP was investigated in vitro using pig gastric H+-K+-ATPase-enriched membrane vesicles. TMP acutely increased natriuresis and decreased kaliuresis, confirming its ENaC-inhibiting property. Under control diet conditions, TMP had no effect on urinary pH or acid excretion. Interestingly, K+ depletion unmasked an acute urine alkalizing effect of TMP. This finding was corroborated by in vitro experiments showing that TMP inhibits H+-K+-ATPase activity, albeit at much higher concentrations than benzamil. In conclusion, under control diet conditions, TMP inhibited ENaC function without changing urinary H+ excretion. This finding further supports the hypothesis that the inhibition of ENaC per se does not impair H+ excretion in the collecting duct. Moreover, TMP-induced urinary alkalization in animals fed a low-K+ diet highlights the importance of renal H+-K+-ATPase-mediated H+ secretion in states of K+ depletion.

KW - Acidosis/metabolism

KW - Animals

KW - Anti-Bacterial Agents/pharmacology

KW - Epithelial Sodium Channels/metabolism

KW - H(+)-K(+)-Exchanging ATPase/metabolism

KW - Kidney Tubules, Collecting/metabolism

KW - Mice

KW - Sodium/metabolism

KW - Swine

KW - Trimethoprim/pharmacology

KW - metabolic acidosis

KW - sulfamethoxazole

KW - benzamil

KW - epithelial Na+ channel

U2 - 10.1152/ajprenal.00273.2023

DO - 10.1152/ajprenal.00273.2023

M3 - Journal article

C2 - 37942538

SN - 1931-857X

VL - 326

SP - F143-F151

JO - American journal of physiology. Renal physiology

JF - American journal of physiology. Renal physiology

IS - 1

ER -

Trimethoprim inhibits renal H+/K+ ATPase in states of K+ depletion

Abstract

Adgang til dokumentet

Fingeraftryk

Citationsformater