Klotho Deficiency Induces Arteriolar Hyalinosis in a Trade-Off with Vascular Calcification.

Autor:	Mencke R; Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Department of Neurosurgery, Carl von Ossietzky University of Oldenburg, Oldenburg, Germany., Umbach AT; Department of Physiology I, Eberhard-Karls-Universität, Tübingen, Germany., Wiggenhauser LM; Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands., Voelkl J; Department of Physiology I, Eberhard-Karls-Universität, Tübingen, Germany., Olauson H; Division of Renal Medicine, Department of Clinical Science, Intervention, and Technology, Karolinska Institute, Stockholm, Sweden., Harms G; Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands., Bulthuis M; Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands., Krenning G; Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands., Quintanilla-Martinez L; Department of Pathology, Eberhard Karls University of Tübingen, Tübingen, Germany., van Goor H; Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands., Lang F; Department of Physiology I, Eberhard-Karls-Universität, Tübingen, Germany., Hillebrands JL; Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. Electronic address: j.l.hillebrands@umcg.nl.
Jazyk:	angličtina
Zdroj:	The American journal of pathology [Am J Pathol] 2019 Dec; Vol. 189 (12), pp. 2503-2515. Date of Electronic Publication: 2019 Sep 17.
DOI:	10.1016/j.ajpath.2019.08.006
Abstrakt:	Hyalinosis is a vascular lesion affecting the renal vasculature and contributing to aging-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 aging. Histochemistry was used to assess hyalinosis in Klotho -/- kidneys, compared with 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, whereas 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 (SMCs). 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 SMC dedifferentiation. In the absence of a calcification-inducing stimulus, SMCs 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 aging-related arteriolar hyalinosis. (Copyright © 2019 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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