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Klotho deficiency induces arteriolar hyalinosis in a trade-off with vascular calcification.

Authors
  • Mencke, Rik1
  • Umbach, Anja T2
  • Wiggenhauser, Lucas M3
  • Voelkl, Jakob2
  • Olauson, Hannes4
  • Harms, Geert3
  • Bulthuis, Marian3
  • Krenning, Guido3
  • Quintanilla-Martinez, Leticia5
  • van Goor, Harry3
  • Lang, Florian2
  • Hillebrands, Jan-Luuk6
  • 1 Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Universitätsklinik für Neurochirurgie, Carl von Ossietzky Universität Oldenburg, Oldenburg, Germany. , (Germany)
  • 2 Department of Physiology I, Eberhard-Karls-Universität, Tübingen, Germany. , (Germany)
  • 3 Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. , (Netherlands)
  • 4 Department of Clinical Science, Intervention, and Technology (Division of Renal Medicine), Karolinska Institutet, Stockholm, Sweden. , (Sweden)
  • 5 Department of Pathology, Eberhard-Karls-Universität, Tübingen, Germany. , (Germany)
  • 6 Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. Electronic address: [email protected] , (Netherlands)
Type
Published Article
Journal
American Journal Of Pathology
Publisher
Elsevier
Publication Date
Sep 17, 2019
Identifiers
DOI: 10.1016/j.ajpath.2019.08.006
PMID: 31539519
Source
Medline
Language
English
License
Unknown

Abstract

Hyalinosis is a vascular lesion affecting the renal vasculature and contributing to ageing-related renal function decline. We assessed whether arteriolar hyalinosis is caused by Klotho deficiency - a state known to induce both renal and vascular phenotypes associated with ageing. Histochemistry was used to assess hyalinosis in Klotho-/- kidneys, compared to Klotho+/- and wild-type littermates. Immunohistochemistry was used to investigate vascular lesion composition and the different layers of the vascular wall. Finally, spironolactone was used to inhibit calcification in kl/kl mice and vascular lesions were characterized in the kidney. Arteriolar hyalinosis was detected in Klotho-/- mice, which was present up to the afferent arterioles. Hyalinosis was accompanied by loss of α-smooth muscle actin expression, while the endothelial lining was mostly intact. Hyalinous lesions were positive for IgM and iC3b/c/d, indicating subendothelial leakage of plasma proteins. The presence of extracellular matrix proteins suggested increased production by smooth muscle cells. Finally, in Klotho-/- mice with marked vascular calcification, treatment with spironolactone allowed for replacement of calcification by hyalinosis. Klotho deficiency potentiates both endothelial hyperpermeability and smooth muscle cell de-differentiation. Absent a calcification-inducing stimulus, smooth muscle cells assume a synthetic phenotype in response to subendothelial leakage of plasma proteins. In the kidney, this results in arteriolar hyalinosis, which contributes to the decline in renal function. Klotho may play a role in preventing ageing-related arteriolar hyalinosis. Copyright © 2019. Published by Elsevier Inc.

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