Inhibition of cyclooxygenase-2 in hematopoietic cells results in salt-sensitive hypertension
Ming-Zhi Zhang, … , Xiaofeng Fan, Raymond C. Harris
Ming-Zhi Zhang, … , Xiaofeng Fan, Raymond C. Harris
Published October 20, 2015
Citation Information: J Clin Invest. 2015;125(11):4281-4294. https://doi.org/10.1172/JCI81550.
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Research Article Nephrology

Inhibition of cyclooxygenase-2 in hematopoietic cells results in salt-sensitive hypertension

Abstract

Inhibition of prostaglandin (PG) production with either nonselective or selective inhibitors of cyclooxygenase-2 (COX-2) activity can induce or exacerbate salt-sensitive hypertension. This effect has been previously attributed to inhibition of intrinsic renal COX-2 activity and subsequent increase in sodium retention by the kidney. Here, we found that macrophages isolated from kidneys of high-salt–treated WT mice have increased levels of COX-2 and microsomal PGE synthase–1 (mPGES-1). Furthermore, BM transplantation (BMT) from either COX-2–deficient or mPGES-1–deficient mice into WT mice or macrophage-specific deletion of the PGE2 type 4 (EP4) receptor induced salt-sensitive hypertension and increased phosphorylation of the renal sodium chloride cotransporter (NCC). Kidneys from high-salt–treated WT mice transplanted with Cox2–/– BM had increased macrophage and T cell infiltration and increased M1- and Th1-associated markers and cytokines. Skin macrophages from high-salt–treated mice with either genetic or pharmacologic inhibition of the COX-2 pathway expressed decreased M2 markers and VEGF-C production and exhibited aberrant lymphangiogenesis. Together, these studies demonstrate that COX-2–derived PGE2 in hematopoietic cells plays an important role in both kidney and skin in maintaining homeostasis in response to chronically increased dietary salt. Moreover, these results indicate that inhibiting COX-2 expression or activity in hematopoietic cells can result in a predisposition to salt-sensitive hypertension.

Authors

Ming-Zhi Zhang, Bing Yao, Yinqiu Wang, Shilin Yang, Suwan Wang, Xiaofeng Fan, Raymond C. Harris

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Figure 1

Genetic or pharmacologic COX-2 inhibition led to salt-sensitive hypertension.

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Genetic or pharmacologic COX-2 inhibition led to salt-sensitive hyperten...
(A) SBP was elevated in mice (male, 129/SvJ) treated with a high-salt diet plus a selective COX-2 inhibitor, SC58236, but not in mice with a high-salt diet alone. *P < 0.05 vs. control and high-salt diet alone. n = 4 in each group. (B) WT and Cox2–/– mice (male, 2 months old, C57BL/6) were treated with a low-salt diet, normal-salt diet, or high-salt diet for 4 weeks, consecutively. SBP was similar between WT and Cox2–/– mice on a low-salt diet. Increasing dietary salt intake had no effect on SBP in WT mice, but led to progressive increases in SBP in Cox2–/– mice. *P < 0.05 vs. WT on a normal-salt diet; ***P < 0.001 vs. WT on a high-salt diet; †P < 0.05 vs. Cox2–/– on a normal-salt diet, n = 5 in each group. All values are shown as mean ± SEM. All P values were calculated by Student’s t test.