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Tamm-Horsfall Protein Regulates Mononuclear Phagocytes in the Kidney.

Authors
  • Micanovic, Radmila1
  • Khan, Shehnaz1
  • Janosevic, Danielle1
  • Lee, Maya E1
  • Hato, Takashi1
  • Srour, Edward F1, 2
  • Winfree, Seth1
  • Ghosh, Joydeep1
  • Tong, Yan3
  • Rice, Susan E1
  • Dagher, Pierre C1, 4
  • Wu, Xue-Ru5
  • El-Achkar, Tarek M6, 4
  • 1 Departments of Medicine.
  • 2 Microbiology and Immunology, and.
  • 3 Biostatistics, Indiana University, Indianapolis, Indiana. , (India)
  • 4 Department of Medicine, Roudebush Veterans Affairs Medical Center, Indianapolis, Indiana; and. , (India)
  • 5 Departments of Urology and Pathology, New York University and Manhattan Veterans Affairs, New York, New York.
  • 6 Departments of Medicine, [email protected]
Type
Published Article
Journal
Journal of the American Society of Nephrology
Publisher
American Society of Nephrology
Publication Date
Mar 01, 2018
Volume
29
Issue
3
Pages
841–856
Identifiers
DOI: 10.1681/ASN.2017040409
PMID: 29180395
Source
Medline
Keywords
License
Unknown

Abstract

Tamm-Horsfall protein (THP), also known as uromodulin, is a kidney-specific protein produced by cells of the thick ascending limb of the loop of Henle. Although predominantly secreted apically into the urine, where it becomes highly polymerized, THP is also released basolaterally, toward the interstitium and circulation, to inhibit tubular inflammatory signaling. Whether, through this latter route, THP can also regulate the function of renal interstitial mononuclear phagocytes (MPCs) remains unclear, however. Here, we show that THP is primarily in a monomeric form in human serum. Compared with wild-type mice, THP-/- mice had markedly fewer MPCs in the kidney. A nonpolymerizing, truncated form of THP stimulated the proliferation of human macrophage cells in culture and partially restored the number of kidney MPCs when administered to THP-/- mice. Furthermore, resident renal MPCs had impaired phagocytic activity in the absence of THP. After ischemia-reperfusion injury, THP-/- mice, compared with wild-type mice, exhibited aggravated injury and an impaired transition of renal macrophages toward an M2 healing phenotype. However, treatment of THP-/- mice with truncated THP after ischemia-reperfusion injury mitigated the worsening of AKI. Taken together, our data suggest that interstitial THP positively regulates mononuclear phagocyte number, plasticity, and phagocytic activity. In addition to the effect of THP on the epithelium and granulopoiesis, this new immunomodulatory role could explain the protection conferred by THP during AKI.

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