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

doi:10.1073/pnas.0711283105

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

*Department of Medicine, Georgetown University, Washington, DC 20057;
^‡Departments of Internal Medicine and Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390;
^§Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215; and
^¶Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201

Edited by Maurice B. Burg, National Institutes of Health, Bethesda, MD, and approved March 7, 2008 (received for review November 30, 2007)

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 significantly 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.

Footnotes

^†To whom correspondence may be addressed at:
Department of Medicine, Georgetown University, Box 571412, Washington, DC, 20057-1412.
E-mail: st285{at}georgetown.edu
^‖To whom correspondence may be addressed. E-mail: ecelbarc{at}georgetown.edu
Author contributions: S.T. and C.M.A.E. designed research; S.T., N.S., P.S.G., and J.B.W. performed research; P.I. and C.R.K. contributed new reagents/analytic tools; S.T., P.S.G., J.B.W., and C.M.A.E. analyzed data; and S.T. and C.M.A.E. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.