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

Table 2 Summary of the protective effects of different klotho regulators in different sepsis models

Klotho regulator	Sepsis model	Mechanism	Effect	Ref.
Treated mice with klotho protein (0.02 mg/kg) for 4 days	LPS	Klotho administration/attenuates the reactive oxygen species/p38-mitogen activated protein kinase signaling pathway	Reversal of myocardial injury. Reduction in atrial and brain natriuretic peptide (atrial natriuretic peptide and BNP). Reduction in apoptosis	Yan et al[31]
Recombinant klotho protein	CLP	Restoration of endogenous klotho expression	Alleviated CLP-induced acute renal injury by reducing serum creatinine and BUN levels	Chen et al[13]
Recombinant klotho protein	LPS	Klotho administration/suppression of NF-κB activation	Cardiac function was improved. Lower myocardial levels of chemokines and cytokines TNF-α, IL-6, and IL-1β	Hui et al[25]
Recombinant klotho protein	LPS	Anti-inflammatory effect of klotho administration/suppression of IL-6 and adhesion molecules	Return to the baseline levels for myocardial ICAM-1, VCAM-1, and IL-6. Recovery from cardiac dysfunction	Li et al[22]
Recombinant IL-37	LPS	Anti-inflammatory effect of IL-37/klotho upregulation/suppression of IL-6 and adhesion molecules	Improvement of cardiac functions	Li et al[22]
Pretreatment-recombinant α-klotho protein	LPS	Antiapoptotic mechanism through caspase-3 reduction. Anti-inflammatory by shifting the balance towards an anti-inflammatory environment. Antioxidant activities	Amelioration of septic cardiorenal injury. Reduction in serum levels of troponin, NGAL, BNP, and creatinine. Reduction in the renal cytokines IL-6, IL-1, and TNF-α levels, with marked elevation in IL-10. Reduction in malondialdehyde and nitric oxide production	Liu et al[41]
Recombinant human-klotho protein	CLP. LPS in-vitro study in the human HK2 epithelial cell line	Klotho exerts its protective effects by upregulating nuclear factor erythroid related factor 2 to suppress the ferroptosis signaling pathway	Alleviated kidney injury and increased HK2 cell viability. Administration of klotho upregulates klotho expression in blood, renal tissue, and HK2 cells. Low levels of the inflammatory factors TNF-α and IL-6 and oxidative stress responses. Improvement in mitochondrial number, structure, and function in HK2 cells	Zhou et al[14]
Recombinant α-klotho protein	In-vitro LPS administration to HPAEpiCs. CLP in-vivo	Prevents activation of the Bcl-2/Bax/caspase-3 signaling pathway	Klotho increased mouse survival and decreased IL-1β, IL-6, and TNF-α levels. Reducing the percentage of apoptotic cells in lung tissue and HPAEpiCs exposed to LPS	Li et al[42]
Treatment with human Wharton’s Jelly-Derived Mesenchymal Stem Cells	CLP	Klotho protein expression was high. Reduction in NF-κB tissue expression. Expression of Bax was reduced, whereas Bcl-X was increased	Survival was improved. Glomerular filtration rate and renal and liver functions were improved. Reduction in apoptosis. Levels of the proinflammatory cytokines IL-1α, IL-6, interferon-γ, and TNF-α were reduced. Endothelial function was improved	Cóndor et al[23]
Resveratrol and Recombinant murine α-klotho protein	CLP	Increased tissue expression of klotho protein in both treated groups. The expression of Bax and caspase-3 was reduced, whereas that of Bcl-2 was increased. The reno-protective effect exerted by klotho is through the antiapoptotic effect	Resveratrol has the same effect as exogenous administration of the klotho protein. Improvement in renal function and structure, decrease in serum creatinine and BUN	Chen et al[35]
Recombinant klotho protein	LPS	Reduced level of myeloid peroxidase. Attenuation of renal and brain E-selectin, VCAM-1, ICAM-1 mRNA, endothelial adhesion molecule expression, and neutrophil infiltration	Renal and brain inflammation were reduced. Low plasma BUN and plasma NGAL levels. Decreased renal and brain levels of IL-6, IL-1β, IL-8 and TNF-α	Jou-Valencia et al[38]

BNP: Brain natriuretic peptide; BUN: Blood urea nitrogen; CLP: Cecal ligation and puncture; HK2: Renal tubular; HPAEpiCs: Human pulmonary alveolar epithelial cells; ICAM-1: Intracellular adhesion molecule-1; IL: Interleukin; LPS: Lipopolysaccharide; NF-κB: Nuclear factor-kappa β; NGAL: Neutrophil gelatinase-associated lipocalin; TNF-α: Tumor necrosis factor-α; VCAM-1: Vascular cell adhesion molecule.