Abstract: SA-PO399

Fludrocortisone Time-Dependently Up-Regulates Erythropoietin (Epo) mRNA Expression via HIF2α Pathway in Rat Kidney

Session Information

Category: Fluid, Electrolytes, and Acid-Base

  • 702 Water/Urea/Vasopressin, Organic Solutes

Authors

  • Nonoguchi, Hiroshi, Kitasato University Medical Center, Kitamoto, Saitama, Japan
  • Sato, Yuichi, Kitasato University, Sagamihara, Japan
  • Kawahara, Katsumasa, Dept of Physiol, Kitasato Univ School of Med, Sagamihara, Japan
  • Yasuoka, Yukiko, Dept of Physiol, Kitasato Univ School of Med, Sagamihara, Japan
  • Izumi, Yuichiro, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan
  • Nakayama, Yushi, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan
  • Inoue, Hideki, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan
  • Nagai, Takanori, Hyogo College of Medicine, Nishinomiya, Japan
  • Nanami, Masayoshi, Hyogo College of Medicine, Nishinomiya, Japan
  • Nakanishi, Takeshi, Hyogo College of Medicine, Nishinomiya, Japan
  • Mukoyama, Masashi, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan
Background

Epo is produced by the kidney in response to hypoxia and anemia via stimulation of hypoxia-inducible factor 2α (HIF2α). Although renin-angiotensin-aldosterone system (RAS) blocker-induced renal anemia strongly suggests the participation of RAS on Epo production, no hormonal studies of Epo production have been conducted. Therefore, we investigated the effects of fludrocortisone, an analogue of aldosterone, on Epo mRNA expression in the rat kidney.

Methods

Male SD rats were given intraperitoneal injection of fludrocortisone 2.5 mg/100 g BW/day. At 2, 4, 6 and 72 hr, the kidney was removed and RNA was extracted for real time PCR. We also used tubule suspensions of renal cortex to test the direct effects of aldosterone (10-9 and 10-6 M) on Epo mRNA expression. Tubule suspensions were incubated w/ or w/o aldosterone in 2 hr. Plasma Epo concentration was also measured using CLEIA.

Results

In kidney cortex, the Epo mRNA expression was increased by 3-fold at 4 hr and decreased to very low level at 72 hr after the injection of fludrocortisone. The levels of HIF2α, HIF1α and PHD2 mRNA expressions also changed in the same time course. In tubule suspension, the Epo and HIF2α mRNA expression levels became nearly zero after 3 hr-incubation. It was restored by 2-hr incubation with aldosterone, together with the increase of HIF2 α, HIF1α, mineralocorticoid receptor, GATA2 and GATA3 mRNA expressions. Plasma Epo concentrations were increased from 1.10 ± 0.4 to 2.22 ± 0.17 mIU/ml (n=5, p<0.05) at 6 hr after the injection of fludrocortisone, but was decreased to 1.62 ± 0.43 U/ml (n=10, p>0.05) at 72 hr.

Conclusion

Aldosterone may regulate Epo production by the nephron via stimulation of a HIF2α pathway. HIF2α is regulated not only by hypoxia but also by RAS.

Funding

  • Commercial Support