Klotho in vascular biology

Abstract

Klotho is a protein named for the Greek goddess who spins the thread of life. This is a fitting name, as the Klotho protein has been characterized as an anti-ageing factor. Klotho is mainly produced in the kidney. Loss of Klotho in mice has long been known to lead to vascular calcification, similar to patients with chronic kidney disease, who have a severly limited Klotho production capacity. My thesis focuses on the relationship between Klotho and blood vessels. We first assessed whether Klotho protein is expressed in blood vessels, which we could not detect using various methods, except for a very low level of Klotho mRNA (which codes for the protein). We then found that blood vessels in mice that specifically cannot produce Klotho in blood vessels cannot relax as readily as healthy mouse blood vessels, suggesting a physiological role for low Klotho levels. We also assessed whether we should be looking into a supposed different Klotho protein form, secreted Klotho, which we then found does not exist at all and is therefore irrelevant to the vasculature. We also investigated what effect Klotho has on blood vessels. We further characterized the vascular calcification that occurs in Klotho deficiency, we found that Klotho deficiency leads to a vascular condition seen in ageing called arteriolar hyalinosis, to the thickening of the innermost layer of arteries, and to worse vessel relaxation reactions. We identified Klotho as a promising inhibitor of tumour angiogenesis. We finally tried to identify obstacles and opportunities for Klotho to be used clinically