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Glucocorticoids improve renal responsiveness to atrial natriuretic peptide by up-regulating natriuretic peptide receptor-A expression in the renal inner medullary collecting duct in decompensated heart failure.

Abstract
In heart failure, the renal responsiveness to exogenous and endogenous atrial natriuretic peptide (ANP) is blunted. The mechanisms of renal hyporesponsiveness to ANP are complex, but one potential mechanism is decreased expression of natriuretic peptide receptor-A (NPR-A) in inner medullary collecting duct (IMCD) cells. Newly emerging evidence shows that glucocorticoids could produce potent diuresis and natriuresis in patients with heart failure, but the precise mechanism is unclear. In the present study, we found dexamethasone (Dex) dramatically increased the expression of NPR-A in IMCD cells in vitro. The NPR-A overexpression induced by Dex presented in a time- and dose-dependent manner, which emerged after 12 h and peaked after 48 h. The cultured IMCD cells were then stimulated with exogenous rat ANP. Consistent with the findings with NPR-A expression, Dex greatly increased cGMP (the second messenger for the ANP) generation in IMCD cells, which presented in a time- and dose-dependent manner as well. In rats with decompensated heart failure, Dex dramatically increased NPR-A expression in inner renal medulla, which was accompanied by a remarkable increase in renal cGMP generation, urine flow rate, and renal sodium excretion. It is noteworthy that Dex dramatically lowered plasma ANP, cGMP levels, and left ventricular end diastolic pressure. These favorable effects induced by Dex were glucocorticoid receptor (GR)-mediated and abolished by the GR antagonist 17β-hydroxy-11β-[4-dimethylamino phenyl]-17α-[1-propynyl]estra-4,9-dien-3-one (RU486). Collectively, glucocorticoids could improve renal responsiveness to ANP by up-regulating NPR-A expression in the IMCD and induce a potent diuretic action in rats with decompensated heart failure.
AuthorsChao Liu, Ying Chen, Yunxiao Kang, Zhihua Ni, Heming Xiu, Jing Guan, Kunshen Liu
JournalThe Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 339 Issue 1 Pg. 203-9 (Oct 2011) ISSN: 1521-0103 [Electronic] United States
PMID21737535 (Publication Type: Journal Article)
Chemical References
  • Glucocorticoids
  • Hormone Antagonists
  • Mifepristone
  • Atrial Natriuretic Factor
  • Sodium
  • Receptors, Atrial Natriuretic Factor
  • atrial natriuretic factor receptor A
  • Cyclic GMP
Topics
  • Animals
  • Atrial Natriuretic Factor (biosynthesis, blood, urine)
  • Blotting, Western
  • Cell Separation
  • Cells, Cultured
  • Cyclic GMP (blood, metabolism, urine)
  • Diuresis (drug effects)
  • Glomerular Filtration Rate (drug effects)
  • Glucocorticoids (pharmacology)
  • Heart Failure (physiopathology)
  • Hormone Antagonists (pharmacology)
  • Kidney (drug effects, metabolism)
  • Kidney Medulla (drug effects, metabolism)
  • Kidney Tubules, Collecting (drug effects, metabolism)
  • Male
  • Mifepristone (pharmacology)
  • Natriuresis (drug effects)
  • Rats
  • Rats, Wistar
  • Receptors, Atrial Natriuretic Factor (biosynthesis)
  • Sodium (urine)
  • Stroke Volume (drug effects)
  • Up-Regulation (drug effects)
  • Urodynamics (drug effects)

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