Abstract: SA-PO1074

Uncoupled Endothelial Nitric Oxide Synthase (eNOS) in the Kidney Correlates with Increased Blood Pressure (BP) in Insulin-Infused Mice

Session Information

Category: Hypertension

  • 1102 Hypertension: Basic and Experimental - Renal Causes and Consequences

Authors

  • Ecelbarger, Carolyn M., Georgetown University, Washington, District of Columbia, United States
  • Alunan, Ashley, Willamette University, Salem, Oregon, United States
  • Lee, Hwal, Georgetown University, Washington, District of Columbia, United States
  • Fluitt, Maurice, Georgetown University, Washington, District of Columbia, United States
  • Tiwari, Swasti, SGPGIMS, Lucknow, India
  • Li, Lijun, Georgetown University, Washington, District of Columbia, United States
Background

Insulin stimulates NO production in the kidney via activation of eNOS which may lower BP; however, whether and how insulin resistance alters this relationship is unclear.

Methods

We tested whether insulin infusion into insulin-sensitive (C57Bl/6, “C57”) versus insulin-resistant (TALLYHO, “TH”) mice resulted in differential BP responses and renal eNOS regulation. Male mice (4-6 months old) were infused with insulin (50 U/kg●bw/d) by osmotic minipump for 14 days (some mice were maintained as untreated). One-half of the infused mice in each strain were switched from a normal NaCl diet (NSD, 1%) to a high-NaCl diet (HSD, 4%) at day 7 of the infusion (n = 6-8/group).

Results

Mean arterial BP (MAP), measured by radiotelemetry, was 10-15 mm Hg lower in C57 mice (relative to TH) at baseline, fell days 2-5 of infusion, then rose days 7-14, so that by day 14, it was no longer different from TH. Pulse pressure (PP) was constant. In TH, MAP was relatively resistant to insulin, while PP fell (~40%). Light-to-dark ratio of MAP (indicator of diurnal rhythm) was elevated in TH in the baseline and increased in both strains with HSD. Urine was measured for nitrites plus nitrates (NOx) at baseline and days 1, 7, and 14 of the infusion. Mean urine NOx increased in both strains (30-40%) between baseline and day 1, but fell to ~55% of baseline by day 14. Plasma NOx concentration was significantly higher in untreated TH (relative to C57), but fell ~40% with insulin infusion (with either NSD or HSD). In contrast, plasma NOx rose in C57 with insulin infusion (13%) and an additional 23% with insulin plus HSD. NOS activity (per mg tissue) was increased by insulin infusion in renal cortex (CTX) in both strains, but in the medulla the increase was restricted to the C57. Western blotting of kidney revealed that coupled (150 KDa) and uncoupled (120 KDa) eNOS band densities were higher in TH, and insulin plus HSD substantially increased the uncoupled band especially in TH.

Conclusion

In summary, insulin infusion for 14 days abrogates BP differences between C57 and TH mice suggesting hyperinsulinemia may primarily underlie the modest hypertension in TH mice. Furthermore, progressive renal eNOS uncoupling and impaired NO production may play a role in the development of hypertension associated with insulin resistance.

Funding

  • Clinical Revenue Support