FP089ARTERIOLAR HYALINOSIS IN KLOTHO DEFICIENCY

INTRODUCTION AND AIMS: Arteriolar hyalinosis is a vascular lesion affecting the renal vasculature in ageing, hypertension, and after transplantation. It is thought to contribute to renal function decline. We wanted to assess whether arteriolar hyalinosis is caused by Klotho deficiency - a state known to induce both renal and vascular ageing-related pathologies. METHODS: The presence of hyalinosis was assessed in kidneys from 7-week-old Klotho-/-, Klotho+/-, and WT mice. We used (immuno)histochemistry to investigate the composition of the lesions and the different layers of the vascular wall. Finally, using kl/kl mice (with a promoter disruption rather than the exon deletion of Klotho-/- mice and with more severe vascular calcification) we assessed the effect of spironolactone treatment (80 mg/L in drinking water, between 3 and 8 weeks of age) on the vascular lesions in the kidney as spironolactone inhibits vascular calcification. RESULTS: We detected marked arteriolar hyalinosis in Klotho-/- mice, present up to the afferent arterioles. Hyalinosis was accompanied by local 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 increased presence of extracellular matrix proteins suggests increased production by smooth muscle cells and the gain of S100A4 expression indicates smooth muscle cell de-differentiation towards a synthetic phenotype. In kl/kl mice, spironolactone treatment inhibited the development of calcification and resulted in the development of hyalinosis. CONCLUSIONS: Klotho deficiency induces the development of hyalinosis: spontaneously in Klotho-/- mice and after inhibition of calcification in kl/kl mice, also attesting to the phenotypic variability of Klotho deficiency. Klotho deficiency potentiates both endothelial hyperpermeability and smooth muscle cell de-differentiation to a synthetic phenotype, likely in response to subendothelial leakage of plasma proteins. Klotho may play a role in preventing ageing-related or calcineurin inhibitor-induced arteriolar hyalinosis.