Klotho: A multifaceted protector in sepsis-induced organ damage and a potential therapeutic target

Table 1 Effect of klotho downregulation on sepsis models

Klotho regulator	Sepsis model	Mechanism	Effect	Ref.
Aged mice	LPS	Klotho downregulation/upregulation of NF-κB	Cardiovascular dysfunction. Higher myocardial levels of cytokines TNF-α, IL-6, and IL-1β	Hui et al[25]
Aged mice	LPS	Exacerbated inflammation associated with aging/klotho downregulation	More severe and persistent cardiac dysfunction. Higher myocardial IL-6, ICAM-1, and vascular cell adhesion molecule levels	Li et al[22]
Aged mice	CLP	Serum TNF-α and IL-6 were elevated. Caspase-3 tissue expression. The bacterial count increased	The survival rate was reduced. Apoptosis activation in the thymus and spleen. Impairment of innate and adaptive immunity	Inoue et al[43]
Genetically deficient Kl/+ mice	CLP	Klotho downregulation/upregulation of NF-κB	Low survival rate. Increase in the production of TNF-α, IL-1β, IL-6. Increase in thiobarbituric acid reactive substances and lactate with a reduction in reduced glutathione. The autonomic response in sepsis was much more harmful through impairment of the vasopressor effect and baroreflex sensitivity	Jorge et al[28]
Klotho-siRNA fibroblasts. In-vitro study	LPS	Upregulation of superoxide production/downregulation of glutathione antioxidant. Upregulation of high mobility group box-1. Increase in NF-κB activation	Reduction in wound healing. Apoptotic cell death induction. Imbalance in intracellular zinc and calcium amounts. Increased secretion of TNF-α, IL-6, and IL-Iβ, concurrently with suppression of anti-inflammatory cytokine IL-10	Mytych et al[44]
Haploinsufficient mice (Kl+/–)	LPS	Down-regulation in renal and brain klotho gene expression. Elevation in plasma plasma-neutrophil gelatinase-associated lipocalin mRNA level. High mRNA levels of E-selectin, ICAM-1, and retinoic acid-inducible gene-I	Renal and brain damage were observed. Endothelial activation promotes immune cell infiltration into the tissue, which increases tissue damage	Jou-Valencia et al[38]
Klotho knockout mice	CLP	Reduction in klotho level/Hyper-cytokinemia. Impairment of bacterial clearance	Decrease in survival rate when compared to the wild-type. Activation of innate immune cells. Elevation of apoptosis in lymphocytes. Increasing serum concentrations of TNF-α, IL-6, and monocyte chemoattractant protein	Inoue et al[45]
Adult mice	CLP	Reduction in klotho level	Increase in serum creatine and blood urea nitrogen. Damage to renal tissue. Autophagy activation	Chen et al[46]

CLP: Cecal ligation and puncture; ICAM-1: Intracellular adhesion molecules; IL: Interleukin; LPS: Lipopolysaccharide; NF-κB: Nuclear factor-kappa β; TNF-α: Tumor necrosis factor-α.