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- Title
Inhibition of cyclooxygenase-2 in hematopoietic cells results in salt-sensitive hypertension.
- Authors
Ming-Zhi Zhang; Bing Yao; Yinqiu Wang; Shilin Yang; Suwan Wang; Xiaofeng Fan; Harris, Raymond C.; Zhang, Ming-Zhi; Yao, Bing; Wang, Yinqiu; Yang, Shilin; Wang, Suwan; Fan, Xiaofeng
- 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.
- Subjects
CELL metabolism; PROTEIN metabolism; ANIMAL experimentation; CELL receptors; ENZYMES; HETEROCYCLIC compounds; HYPERTENSION; KIDNEYS; MACROPHAGES; MICE; NONSTEROIDAL anti-inflammatory agents; OXIDOREDUCTASES; PHOSPHORYLATION; PROTEINS; RESEARCH funding; SALT; SKIN; SULFONAMIDES; CYCLOOXYGENASE 2; FETAL development; ENDOTHELIAL growth factors; MEMBRANE glycoproteins; IMMUNOCOMPROMISED patients; DINOPROSTONE; PHYSIOLOGY
- Publication
Journal of Clinical Investigation, 2015, Vol 125, Issue 11, p4281
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI81550