Kidney Week

Abstract: TH-OR056

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

Session Information

• Hypertension: Off the Cuff - Treatment and Mechanisms
  November 02, 2017 | Location: Auditorium C, Morial Convention Center
  Abstract Time: 05:30 PM - 05:42 PM

Category: Hypertension

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

Authors

• Zhang, Ming-Zhi, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Ming-Zhi Zhang, MD, FASN



Dr. Ming-zhi Zhang is an Associate Professor of Medicine and Cancer Biology at Vanderbilt University School of Medicine. His research focuses on the role of the interactions of intrarenal hormones (angiotensin II, dopamine, glucocorticoid, et al) and the cyclooxygenase-2 (COX-2) pathway in kidney physiology and pathophysiology. He currently works on the role of renal intrinsic COX-2 in regulation of water and salt homeostasis.

• Niu, Aolei, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Aolei Niu,

• Wang, Yinqiu, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Yinqiu Wang,

• Wang, Suwan, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Suwan Wang,

• Hao, Chuan-Ming, Vanderbilt University Medical Center, Nashville, United States

Chuan-Ming Hao,

• Harris, Raymond C., Vanderbilt University Medical Center, Nashville, Tennessee, United States

Raymond C. Harris,

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-2^f/f (WT) and Tenascin-C-CreER2;COX-2^f/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-2^f/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