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.

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.

Table 3 Summary of clinical data showing the change in klotho expression in septic patients

Sepsis model	Mechanism	Effect	Ref.
Sepsis patients. Collection of warm postmortem biopsies from patients who died of sepsis and renal failure in the ICU	Reduction in renal klotho level. Increased mRNA levels of kidney damage markers neutrophil gelatinase-associated lipocalin and kidney injury molecule-1	Correlated to renal damage	Jou-Valencia et al[38]
Sepsis patients	Reduced serum klotho level	An early predictor of AKI to allow immediate interventions	Pei et al[69]
A prospective cohort of ICU patients with sepsis and previously normal renal function	Low klotho and high erythropoietin plasma levels are cofactors for activating FGF-23	The klotho level is an early predictor of the development of AKI, mortality, and long-term CKD progression in sepsis patients	Toro et al[37]
Patients with CKD are admitted to the ICU with acute inflammation/sepsis	At the peak of infection, suppressing the active form of FGF-23 and activating α-klotho	Counter-regulatory response to acute inflammation	Dounousi et al[62]
Patients admitted to the ICU with septic shock within the previous 72 hours	Increasing serum level of α-klotho	Higher mortality rate	Abdelmalik et al[40]

AKI: Acute kidney injury; CKD: Chronic kidney disease; FGF: Fibroblast growth factor; ICU: Intensive care unit.