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Abstract <p>Nitric oxide (NO) is an important signaling molecule thatregulates numerous physiological processes. Impairment of nitricoxide production and inactivation of genes encoding various NOSisoforms most commonly affect such target organs as the kidneysand liver. The aim of the present study was to investigate kidneyand liver morphology, renal ion-regulating function, and glycemiain adult mice with <i>nos3</i> geneknockout (NOS3 KO). A line of homozygous NOS3 KO mice was generatedon a C57Bl/6 background using CRISPR-Cas9 genome editing technology.In NOS3 KO and wild-type mice aged 3–7 months, glycemia levels and/orurinary sodium excretion were assessed under conditions of freeaccess to food, after a 17-hour fast, and following a salt loadingtest. At the age of 9 months, the animals were euthanized; kidneysand liver were fixed in neutral formalin, followed by standard histologicalprocessing and staining. Under conditions of free access to food,fasting, and in the salt loading test, sodium excretion and thesodium/creatinine ratio did not differ between NOS3 KO and wild-typemice. NOS3 KO mice maintained the corticomedullary structure ofthe kidneys, and no pathological changes were detected. Male NOS3KO mice exhibited reduced liver glycogen stores and a pronounceddecrease in blood glucose levels under fasting conditions. Pharmacologicalcorrection of nitric oxide levels by administration of an NO donor(isosorbide dinitrate) led to an increase in blood glucose levelsin male NOS3 KO mice. Thus, the study demonstrates that mice withan endothelial NO synthase gene knockout maintain normal kidneystructure and function. Male NOS3 KO mice showed a tendency to developfasting hypoglycemia and a reduced glycogen content in hepatocytes,indicating the involvement of NOS3 in the regulation of carbohydratemetabolism.</p>

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Fasting Hypoglycemia and Preserved Renal Function in Endothelial NO Synthase Knockout Mice

  • 期刊论文

  • 发表日期：

    2025年10月1日

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  • A. V. Kutina,
  • G. V. Belyakov,
  • E. V. Balbotkina,
  • P. A. Vishnyakova,
  • A. M. Kosyreva,
  • A. V. Chirinskaite,
  • J. V. Sopova,
  • E. I. Leonova

摘要

Abstract

Nitric oxide (NO) is an important signaling molecule thatregulates numerous physiological processes. Impairment of nitricoxide production and inactivation of genes encoding various NOSisoforms most commonly affect such target organs as the kidneysand liver. The aim of the present study was to investigate kidneyand liver morphology, renal ion-regulating function, and glycemiain adult mice with nos3 geneknockout (NOS3 KO). A line of homozygous NOS3 KO mice was generatedon a C57Bl/6 background using CRISPR-Cas9 genome editing technology.In NOS3 KO and wild-type mice aged 3–7 months, glycemia levels and/orurinary sodium excretion were assessed under conditions of freeaccess to food, after a 17-hour fast, and following a salt loadingtest. At the age of 9 months, the animals were euthanized; kidneysand liver were fixed in neutral formalin, followed by standard histologicalprocessing and staining. Under conditions of free access to food,fasting, and in the salt loading test, sodium excretion and thesodium/creatinine ratio did not differ between NOS3 KO and wild-typemice. NOS3 KO mice maintained the corticomedullary structure ofthe kidneys, and no pathological changes were detected. Male NOS3KO mice exhibited reduced liver glycogen stores and a pronounceddecrease in blood glucose levels under fasting conditions. Pharmacologicalcorrection of nitric oxide levels by administration of an NO donor(isosorbide dinitrate) led to an increase in blood glucose levelsin male NOS3 KO mice. Thus, the study demonstrates that mice withan endothelial NO synthase gene knockout maintain normal kidneystructure and function. Male NOS3 KO mice showed a tendency to developfasting hypoglycemia and a reduced glycogen content in hepatocytes,indicating the involvement of NOS3 in the regulation of carbohydratemetabolism.