autophagy plays a critical role in klotho gene deficiency-induced arterial stiffening and hypertension

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.