Inhibition of cyclooxygenase-2 in hematopoietic cells results in salt-sensitive hypertension
Ming-Zhi Zhang, Bing Yao, Yinqiu Wang, Shilin Yang, Suwan Wang, Xiaofeng Fan, Raymond C. Harris
Ming-Zhi Zhang, Bing Yao, Yinqiu Wang, Shilin Yang, Suwan Wang, Xiaofeng Fan, Raymond C. Harris
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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 3

COX-2 expression modulated monocyte and peritoneal macrophage responses to high-salt intake.

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COX-2 expression modulated monocyte and peritoneal macrophage responses ...
(A) Flow cytometric analysis determined that blood monocyte density was higher in Cox2–/–-WT BMT and mPGES-1–/–-WT BMT mice than in WT-WT BMT mice in response to a high-salt diet. **P < 0.01 vs. high-salt diet–treated WT-WT BMT mice. n = 5. (B) Peritoneal macrophages from high-salt diet–treated Cox2–/–-WT BMT mice had reduced mRNA levels of M2 markers, Ym1, MR, arginase-1, and Tgfb. *P < 0.05; ***P < 0.001 vs. high-salt diet–treated WT-WT BMT mice. n = 5 in each group. All values are shown as mean ± SEM. All P values were calculated by Student’s t test.