Abstract: TH-OR056

Renal Medullary Interstitial Cell COX-2 Protects against Salt-Sensitive Hypertension and Papillary Necrosis

Session Information

Category: Hypertension

  • 1101 Hypertension: Basic and Experimental - Neural and Inflammatory Mechanisms

Authors

  • Zhang, Ming-Zhi, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Niu, Aolei, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Wang, Yinqiu, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Wang, Suwan, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Hao, Chuan-Ming, Vanderbilt University Medical Center, Nashville, United States
  • Harris, Raymond C., Vanderbilt University Medical Center, Nashville, Tennessee, United States
Background

Cycloxygenase 2 (COX-2)-derived prostaglandins regulate renal hemodynamics and salt and water homeostasis. COX-2 is highly expressed in renal medullary interstitial cell (RMICs). COX-2 inhibition causes blood pressure elevation and papillary necrosis and COX-2 sustains RMIC survival in response to hypertonicity in vitro. However, the role or RMIC COX-2 in vivo in response to stimuli has not yet been definitively studied. We investigated the effect of COX-2 deletion in RMICs on blood pressure and papillary integrity in response to high salt intake.

Methods

We used inducible COX-2 deletion in RMICs in adult mice to avoid any potential developmental abnormalities of the inner medulla/papilla. Male COX-2f/f (WT) and Tenascin-C-CreER2;COX-2f/f (RMIC COX-2-/-) mice were fed a high salt diet, and blood pressure was monitored with tail cuff plethysmography. Mice were sacrificed at 2, 4, 9 weeks. For acute salt loading, mice were IP injected with isotonic saline equivalent to 10% of body weight, placed in metabolic cages, and 4-h urine was collected.

Results

Tamoxifen efficiently induced COX-2 deletion in inner medulla/papilla of the Tenascin-C-CreER2; COX-2f/f mice. Blood pressure was similar between RMIC COX-2-/- mice and WT mice on a normal salt diet. Although blood pressure was not altered in WT mice on a high salt diet, it increased gradually in RMIC COX-2-/- mice, peaked at 4-5 weeks (131 ± 5 vs. 121 ± 4 mmHg, P < 0.05, n = 7), and then progressively decreased to levels significantly lower than corresponding WT. After return to a normal salt diet for 3 weeks, RMIC COX-2-/- mice still had lower blood pressure (101 ± 4 vs. 116 ± 3 mmHg, P < 0.05, n = 4) and a urine concentrating defect (2535 ± 97 vs. 3080 ± 120 mOsm/kg H2O of WT, P < 0.01, n = 6), in association with striking loss of papillae. Increased apoptotic cells in papillae of high salt treated RMIC COX-2-/- mice were seen 2 weeks after high salt intake. In addition, RMIC COX-2-/- mice had impaired pressure natriuresis one week after high salt diet (% of sodium excretion: 69.6 ± 8.9 vs. 98.4 ± 4.7 of WT, P < 0.05, n = 4).

Conclusion

These studies indicate that RMIC COX-2 plays an important role in salt and water homeostasis and provides cytoprotection for papillary structures in response to chronic high salt intake.

Funding

  • NIDDK Support