Impaired sodium excretion and increased blood pressure in mice with targeted deletion of renal epithelial insulin receptor

Swasti Tiwari, Nikhil Sharma, Pritmohinder S. Gill, Peter Igarashi, C. Ronald Kahn, James B. Wade, Carolyn M A Ecelbarger

Research output: Contribution to journalArticle

55 Citations (Scopus)

Abstract

Renal tubule epithelial cells express the insulin receptor (IR); however, their value has not been firmly established. We generated mice with renal epithelial cell-specific knockout of the IR by Cre-recombinase-loxP recombination using a kidney-specific (Ksp) cadherin promoter. KO mice expressed significantly lower levels of IR mRNA and protein in kidney cortex (49-56% of the WT) and medulla (32-47%) homogenates. Immunofluorescence showed the greatest relative reduction in the thick ascending limb and collecting duct cell types. Body weight, kidney weight, and food and water intakes were not different from WT littermates. However, KO mice had significantly increased basal systolic blood pressure (BP, 15 mm Hg higher) as measured by radiotelemetry. In response to a volume load by gavage (20 ml/kg of body weight, 0.9% NaCl, 15% dextrose), KO mice had impaired natriuresis (37 ± 10 versus 99 ± 9 mmol of Na+ per 2 h in WT). Furthermore, volume load led to a sustained increase in BP in KO mice only. In contrast, insulin administration i.p. (0.5 units/kg of body weight) resulted in a significant fall in BP in WT, but not in KO mice. To test the role of reduced renal nitric oxide (NO) production in these responses, basal urinary nitrates plus nitrites excretion (UNOx) was measured and found to be 61% lower in KO vs. WT mice. Furthermore, acute insulin increased UNOx by 202% in the WT, relative to a signifi-cantly blunted rise (67%) in KO animals. These results illuminate a previously uncharacterized role for renal IR to reduce BP and facilitate sodium and water excretion, possibly via NO production.

Original languageEnglish (US)
Pages (from-to)6469-6474
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number17
DOIs
StatePublished - Apr 29 2008

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Insulin Receptor
Sodium
Blood Pressure
Kidney
Body Weight
Nitric Oxide
Epithelial Cells
Insulin
Kidney Cortex
Natriuresis
Nitrites
Nitrates
Genetic Recombination
Drinking
Fluorescent Antibody Technique
Extremities
Eating
Weights and Measures
Glucose
Messenger RNA

Keywords

  • Diabetes
  • Metabolic syndrome
  • Natriuresis
  • Volume expansion

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Impaired sodium excretion and increased blood pressure in mice with targeted deletion of renal epithelial insulin receptor. / Tiwari, Swasti; Sharma, Nikhil; Gill, Pritmohinder S.; Igarashi, Peter; Kahn, C. Ronald; Wade, James B.; Ecelbarger, Carolyn M A.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 105, No. 17, 29.04.2008, p. 6469-6474.

Research output: Contribution to journalArticle

Tiwari, Swasti ; Sharma, Nikhil ; Gill, Pritmohinder S. ; Igarashi, Peter ; Kahn, C. Ronald ; Wade, James B. ; Ecelbarger, Carolyn M A. / Impaired sodium excretion and increased blood pressure in mice with targeted deletion of renal epithelial insulin receptor. In: Proceedings of the National Academy of Sciences of the United States of America. 2008 ; Vol. 105, No. 17. pp. 6469-6474.
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abstract = "Renal tubule epithelial cells express the insulin receptor (IR); however, their value has not been firmly established. We generated mice with renal epithelial cell-specific knockout of the IR by Cre-recombinase-loxP recombination using a kidney-specific (Ksp) cadherin promoter. KO mice expressed significantly lower levels of IR mRNA and protein in kidney cortex (49-56{\%} of the WT) and medulla (32-47{\%}) homogenates. Immunofluorescence showed the greatest relative reduction in the thick ascending limb and collecting duct cell types. Body weight, kidney weight, and food and water intakes were not different from WT littermates. However, KO mice had significantly increased basal systolic blood pressure (BP, 15 mm Hg higher) as measured by radiotelemetry. In response to a volume load by gavage (20 ml/kg of body weight, 0.9{\%} NaCl, 15{\%} dextrose), KO mice had impaired natriuresis (37 ± 10 versus 99 ± 9 mmol of Na+ per 2 h in WT). Furthermore, volume load led to a sustained increase in BP in KO mice only. In contrast, insulin administration i.p. (0.5 units/kg of body weight) resulted in a significant fall in BP in WT, but not in KO mice. To test the role of reduced renal nitric oxide (NO) production in these responses, basal urinary nitrates plus nitrites excretion (UNOx) was measured and found to be 61{\%} lower in KO vs. WT mice. Furthermore, acute insulin increased UNOx by 202{\%} in the WT, relative to a signifi-cantly blunted rise (67{\%}) in KO animals. These results illuminate a previously uncharacterized role for renal IR to reduce BP and facilitate sodium and water excretion, possibly via NO production.",
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AU - Kahn, C. Ronald

AU - Wade, James B.

AU - Ecelbarger, Carolyn M A

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AB - Renal tubule epithelial cells express the insulin receptor (IR); however, their value has not been firmly established. We generated mice with renal epithelial cell-specific knockout of the IR by Cre-recombinase-loxP recombination using a kidney-specific (Ksp) cadherin promoter. KO mice expressed significantly lower levels of IR mRNA and protein in kidney cortex (49-56% of the WT) and medulla (32-47%) homogenates. Immunofluorescence showed the greatest relative reduction in the thick ascending limb and collecting duct cell types. Body weight, kidney weight, and food and water intakes were not different from WT littermates. However, KO mice had significantly increased basal systolic blood pressure (BP, 15 mm Hg higher) as measured by radiotelemetry. In response to a volume load by gavage (20 ml/kg of body weight, 0.9% NaCl, 15% dextrose), KO mice had impaired natriuresis (37 ± 10 versus 99 ± 9 mmol of Na+ per 2 h in WT). Furthermore, volume load led to a sustained increase in BP in KO mice only. In contrast, insulin administration i.p. (0.5 units/kg of body weight) resulted in a significant fall in BP in WT, but not in KO mice. To test the role of reduced renal nitric oxide (NO) production in these responses, basal urinary nitrates plus nitrites excretion (UNOx) was measured and found to be 61% lower in KO vs. WT mice. Furthermore, acute insulin increased UNOx by 202% in the WT, relative to a signifi-cantly blunted rise (67%) in KO animals. These results illuminate a previously uncharacterized role for renal IR to reduce BP and facilitate sodium and water excretion, possibly via NO production.

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