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Kidney Week

Abstract: SA-PO1047

Cushing’s Syndrome Increases Renal Sodium Transporters in Urinary Extracellular Vesicles

Session Information

  • Na+, K+, Cl-
    November 04, 2017 | Location: Hall H, Morial Convention Center
    Abstract Time: 10:00 AM - 10:00 AM

Category: Fluid, Electrolytes, and Acid-Base

  • 703 Na+, K+, Cl- Basic

Authors

  • Bovee, Dominique M., Erasmus Medical Center, Rotterdam, Netherlands
  • Salih, Mahdi, Erasmus Medical Center, Rotterdam, Netherlands
  • Danser, Alexander H., Erasmus Medical Center, Rotterdam, Netherlands
  • Zietse, Robert, Erasmus Medical Center, Rotterdam, Netherlands
  • Feelders, Richard, Erasmus Medical Center, Rotterdam, Netherlands
  • Hoorn, Ewout J., Erasmus Medical Center, Rotterdam, Netherlands
Background

Increased renal sodium (Na+) reabsorption contributes to hypertension in Cushing’s syndrome (CS). Renal Na+ transporters can be analyzed non-invasively in urinary extracellular vesicles (uEVs). The aim of this study was to analyze renal Na+ transporters in uEVs of patients with newly diagnosed CS.

Methods

uEVs were isolated by ultracentrifugation and analyzed by immunoblotting in 10 CS patients and 7 age-matched healthy subjects. The majority had an ACTH-producing pituitary adenoma (n=8). In 3 CS patients uEVs were analyzed before and after treatment (unilateral adrenalectomy or ketoconazole). uEVs were isolated without interfering medication (renin-angiotensin system inhibitors or diuretics).

Results

The 10 patients with CS were hypertensive (144 ± 14 / 92 ± 17 mmHg) and had a 2-fold higher abundance of the Na+/H+exchanger type 3 (NHE3) in uEVs compared to healthy controls (p<0.05). CS patients were subsequently divided in those with a suppressed and non-suppressed renin-angiotensin-aldosterone system (RAAS, n=5/group). CS patients with suppressed vs. non-suppressed RAAS had similar blood pressure but significantly lower serum K+ (3.9 ± 0.2 vs. 4.4 ± 0.3 mmol/l, p=0.04). Furthermore, only those with suppressed RAAS had 3- to 4-fold higher phosphorylated Na+-K+-Cl-cotransporter type 2 (pNKCC2) and higher total and phosphorylated Na+-Cl-cotransporter (NCC) in uEVs. Serum K+ but not urinary free cortisol correlated with pNKCC2, pNCC, and NCC in uEVs (r = -0.9, -0.8, and -0.7, respectively; p<0.05 for all). In the 3 CS patients with uEV-analysis before and after treatment, pNKCC2, pNCC, and NCC abundances normalized after treatment in parallel with serum K+. No changes were observed in other uEV proteins of interest, including prostasin (a regulator of the epithelial sodium channel), Rac1 (which reflects mineralocorticoid activity), and aquaporin-2.

Conclusion

CS increases renal Na+ transporter abundance in uEVs especially in patients with suppressed RAAS. In addition to a mineralocorticoid effect of excess glucocorticoids, low serum K+ may also contribute to increased renal Na+ reabsorption and hypertension in CS. Our findings recapitulate previously characterized effects of glucocorticoids on NHE3, NKCC2, and NCC in experimental animals and of mineralocorticoids in patients with primary aldosteronism.