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Abstract <p>Nitric oxide (NO) regulates renal hemodynamics and inhibitstubular sodium reabsorption. NO formation is catalyzed by NO synthases(NOS), and it is important to study the role of individual NO synthasesfor renal functions. The purpose of the study was to obtain a lineof mice with a knockout of the <i>nos3</i> gene(NOS KO) and to evaluate their ion-regulatory renal function. Ahomozygous line of NOS KO mice was developed at the background ofthe C57Bl/6 line using the CRISPR-Cas9 editing method. The physiologicalstudy included 39 animals (10 female and 10 male C57Bl/6 mice; 10female and 9 male NOS KO mice); genotyping was carried out usingPCR and sequencing methods at the age of 4 weeks. To identify differencesin the transport of sodium and potassium in the kidneys of NOS KOmice, experiments were conducted to assess ion excretion in animalswhen given water (control), with a NaCl load (7.7 µmol/g) and withthe administration of a loop diuretic. In the control, no differenceswere detected in the excretion of sodium and potassium ions in NOSKO and C57Bl/6 mice. Under conditions of excess NaCl intake, nosignificant interstrain differences were also revealed: sodium and potassiumexcretion increased by 8.8 and 1.3 times in NOS KO mice and by 8.4and 1.7 times in wild-type mice, respectively. The natriuretic effectof furosemide (5 µg/g) in NOS KO mice was greater than in C57Bl/6mice. Urinary sodium excretion was 4.1 ± 0.3 µmol/g during 2 hoursof observation in NOS KO and 2.7 ± 0.2 µmol/g in wild-type mice(<i>p</i> &lt; 0.001). Thus, the workrevealed for the first time an increase in sensitivity to furosemidein mice with a knockout of the <i>nos3</i> gene,which may indicate the importance of the activity of endothelialNO synthase for the regulation of sodium transport in the thick ascendinglimb of the loop of Henle.</p>

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Nos3 Gene Knockout in Mice Enhances Kidney Sensitivity to Furosemide

  • 期刊论文

  • 发表日期：

    2025年3月1日

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  • A. V. Kutina,
  • G. V. Belyakov,
  • E. V. Balbotkina,
  • A. V. Chirinskaite,
  • J. V. Sopova,
  • E. I. Leonova

摘要

Abstract

Nitric oxide (NO) regulates renal hemodynamics and inhibitstubular sodium reabsorption. NO formation is catalyzed by NO synthases(NOS), and it is important to study the role of individual NO synthasesfor renal functions. The purpose of the study was to obtain a lineof mice with a knockout of the nos3 gene(NOS KO) and to evaluate their ion-regulatory renal function. Ahomozygous line of NOS KO mice was developed at the background ofthe C57Bl/6 line using the CRISPR-Cas9 editing method. The physiologicalstudy included 39 animals (10 female and 10 male C57Bl/6 mice; 10female and 9 male NOS KO mice); genotyping was carried out usingPCR and sequencing methods at the age of 4 weeks. To identify differencesin the transport of sodium and potassium in the kidneys of NOS KOmice, experiments were conducted to assess ion excretion in animalswhen given water (control), with a NaCl load (7.7 µmol/g) and withthe administration of a loop diuretic. In the control, no differenceswere detected in the excretion of sodium and potassium ions in NOSKO and C57Bl/6 mice. Under conditions of excess NaCl intake, nosignificant interstrain differences were also revealed: sodium and potassiumexcretion increased by 8.8 and 1.3 times in NOS KO mice and by 8.4and 1.7 times in wild-type mice, respectively. The natriuretic effectof furosemide (5 µg/g) in NOS KO mice was greater than in C57Bl/6mice. Urinary sodium excretion was 4.1 ± 0.3 µmol/g during 2 hoursof observation in NOS KO and 2.7 ± 0.2 µmol/g in wild-type mice(p < 0.001). Thus, the workrevealed for the first time an increase in sensitivity to furosemidein mice with a knockout of the nos3 gene,which may indicate the importance of the activity of endothelialNO synthase for the regulation of sodium transport in the thick ascendinglimb of the loop of Henle.