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

Rik Mencke, Anja T Umbach, Lucas M Wiggenhauser, Jakob Voelkl, Hannes Olauson, Geert Harms, Marian Bulthuis, Guido Krenning, Leticia Quintanilla-Martinez, Harry van Goor, Florian Lang, Jan-Luuk Hillebrands

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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.

Original languageEnglish
Pages (from-to)2503-2515
Number of pages13
JournalThe American Journal of Pathology
Volume189
Issue number12
Early online date17-Sep-2019
DOIs
Publication statusPublished - Dec-2019

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