TABLE 2.

Regulatory effects of Klotho on autophagy in various diseases, as reported in interventional studies that manipulating Klotho expression.

Organ or tissue	Disease or disease models	Klotho intervention	Intervention strategy	Changes in autophagy indicators	Autophagy activity	Disease outcome
Brain	Alzheimer’s disease Zeng et al. (2019)	↑	Overexpression	LC3II/LC3I ↑, p62 ↓, autolysosome↑	↑	good
	Amyloid-β1-42 fibril-treated BV2 cells Zeng et al., 2019	↑	Overexpression and Recombinant Klotho protein	LC3II/LC3I ↑, p62 ↓	↑	good
Kidney	Basic state of Klotho mutant mice and transgenic mice Shi et al. (2016)	↓	Klotho gene mutant	LC3II/LC3 ↓, p62 ↑	↓	—
		↑	Transgenic mice line	LC3II/LC3I ↑, p62 ↓	↑	—
	Ischemia/reperfusion induced acute kidney injury Shi et al. (2016); Chen et al. (2017)	↓	Klotho gene mutant	LC3II/LC3I ↓, p62 ↑, RFP-LC3 ↓, autolysosome ↓, autophagosomes ↓	↓	poor
		↑	Transgenic mouse line	LC3II/LC3I ↑, p62 ↓, RFP-LC3 ↑, Beclin1/Bcl2 complex ↓, autolysosome↑, autophagosomes ↑	↑	good
		↑	Decrease the methylation of Klotho	Beclin1 ↑, LC3 ↑	↑	good
	Collagen I accumulation in opossum kidney cell Shi et al. (2016)	↑	Recombinant Klotho protein	LC3II/LC3I ↑, p62 ↓	↑	good
	Cecal ligation and puncture-induced acute kidney injury (Chen et al., 2018b)	↑	Recombinant Klotho protein	LC3II/LC3I unchanged, p62 unchanged	unchanged	—
	LPS-treated HK-2 cells Chen et al. (2018b)	↑	Recombinant Klotho protein	LC3II/LC3I unchanged, p62 unchanged	unchanged	—
Tumor	Hepatoma Shu et al. (2013)	↑	Overexpression	LC3II ↑, LC3I ↑	↑	good
	Gastric cancer Xie et al. (2013b)	↑	DNA demethylating agent	LC3II/LC3I ↑	↑	good
	Drug-resistant lung cancer cells Chen et al. (2016)	↑	Overexpression	Beclin1 ↓, LC3II ↓	↓	good
Lung	Cigarette smoke extract-treated murine alveolar macrophage cell line Li et al. (2017b)	↑	Recombinant Klotho protein	LC3II/LC3I ↓	↓	NR
		↓	Klotho-siRNA	LC3II/LC3I ↑	↑	NR
Artery	Hypertension (arterial stiffness) Chen et al. (2015); Chen and Sun (2019)	↓	Klotho gene mutant	LC3II ↑, LC3II/LC3I ↑, Beclin 1 ↑, p62 ↓	↑	poor
	Basic state of mouse vascular aortic smooth muscle cells Chen and Sun (2019)	↑	Recombinant secreted Klotho protein	LC3II/LC3I ↓, Beclin 1 ↓, p62 ↑	↓	—
		↓	Klotho-deficient medium	LC3II ↑, Beclin 1↑, p62 ↓	↑	—
Muscle	Muscular dystrophy (masseter and tongue) Iida et al. (2011)	↓	Klotho gene mutant	LC3II/LC3I ↑, p62 ↓, Gabrap ↑	↑	poor
Islet	T2DM in db/db mice Lin and Sun (2015)	↑	Overexpression	LC3 ↑	↑	good

NR, not reported.