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Abstract: TH-PO481

HIFs in the Renal Medulla Regulate Natriuresis and Blood Pressure Through COX2

Session Information

Category: Fluid and Electrolytes

  • 901 Fluid and Electrolytes: Basic

Author

  • Guan, Nan, Division of Nephrology,Huashan Hospital,Fudan University,Shanghai, Shanghai, China
Background

Hypoxia inducible factors (HIFs) are essential for the maintenance of cellular oxygen homeostasis. In response to hypoxia, stabilized HIFs initiate the expression of genes that alleviate hypoxic stress. HIFs are now important therapeutic targets for CKD anemia. In the phase 2 clinical trial of FG4592(a kind of HIFs stabilizers) in our center, we found that this drug not only corrected anemia but also downregulated blood pressure. Cyclooxygenase 2 (COX2) in the renal medulla was reported to promote natriuresis and decrease blood pressure. HIFs could induce COX2 in some tumors. In the present study we investigated the mechanism underlying the blood pressure lowering effect of HIFs.

Methods

We used mice metabolic cages to measure daily sodium balance. The mice were fed with the same amount of gel food. To capture transient changes in the urine Na+ excretion prior to attainment of a new steady state, daily 8-hour urine were collected after the administration of the drugs. The urinary volume and urinary sodium concentration were measured.

Results

In the clinical trial of FG4592 in our center, patients’ mean blood pressure decreased about 5mmHg compared with basal condition(91.5±1.5mmHg vs. 96.5±1mmHg, P < 0.05,n=10) after 8-week treatment. The administration of FG4592 significantly increased the daily urinary volume and urinary sodium excretion of the mice on high salt diet (8%NaCl). The cumulative sodium excretion of consecutive 4 days was higher in the FG4592 group than the control group(3.77±0.36mmol vs. 2.82±0.25mmol, P < 0.05,n=8). The expression of COX2 in the medulla was increased in the FG4592 group. When we used COX2 inhibitor celecoxib together with FG4592, the natriuresis effect of the latter one was abolished.

Conclusion

HIFs in the renal medulla lower blood pressure through upregulating COX2 and promoting natriuresis.

Funding

  • Clinical Revenue Support