Open AccessAutophagy plays a critical role in Klotho gene deficiency-induced arterial stiffening and hypertension
Author(s) -
Kai Chen,
Zhongjie Sun
Publication year - 2019
Publication title -
journal of molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.708
H-Index - 139
eISSN - 1432-1440
pISSN - 0946-2716
DOI - 10.1007/s00109-019-01841-6
Subject(s) - autophagy , molecular medicine , klotho , medicine , stiffening , human genetics , gene , biology , cardiology , endocrinology , genetics , kidney , apoptosis , civil engineering , cell cycle , engineering
Klotho is an anti-aging gene that shortens the life span when disrupted and extends the lifespan when overexpressed. This study investigated whether autophagy plays a role in Klotho gene deficiency-induced arterial stiffening and hypertension. Klotho mutant heterozygous (KL+/-) mice and age- and sex-matched wild-type (WT) mice were used. Arteries were examined for autophagy using Western blot assays. Pulse wave velocity (PWV), a direct measure of arterial stiffness, and blood pressure (BP) increased significantly in KL (+/-) mice. The autophagy level, as measured by LC3-II expression and autophagy flux, increased in aortas of KL (+/-) mice, indicating that Klotho gene deficiency upregulated autophagy. Chloroquine diminished Klotho gene deficiency-induced increases in PWV and BP and eliminated the upregulation of autophagic flux in KL (+/-) mice. Klotho gene deficiency-induced arterial stiffness was accompanied by upregulation of MMP9, TGFβ-1, TGFβ-3, RUNX2, and ALP, but these changes were effectively mitigated by chloroquine. Chloroquine also halted an increase in scleraxis expression in aortas of Klotho (+/-) mice. In cultured mouse aortic smooth muscle cells, Klotho gene deficiency increased autophagy, leading to upregulation of scleraxis, a key transcription factor of collagen synthesis. Klotho gene deficiency failed to upregulate scleraxis expression when autophagy was inhibited, suggesting that autophagy is a critical mediator of Klotho gene deficiency-induced upregulation of scleraxis. Suppression of enhanced autophagy by chloroquine lessens Klotho gene deficiency-induced arterial stiffening and hypertension by stopping upregulation of MMP9 and scleraxis. The enhanced autophagic activity plays a crucial role in Klotho gene deficiency-induced arterial stiffening and hypertension. KEY MESSAGES: Klotho gene deficiency upregulates autophagy. Upregulation of autophagy plays a role in the pathogenesis of arterial stiffening. Autophagy regulates MMP9 activity and scleraxis expression.