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Am J Physiol Renal Physiol. 2019 Mar 1;316(3):F438-F448. doi: 10.1152/ajprenal.00625.2017. Epub 2018 Dec 5.

Klotho deficiency aggravates sepsis-related multiple organ dysfunction.

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Division of Nephrology, University of São Paulo School of Medicine , São Paulo , Brazil.
Department of Pathology, University of São Paulo School of Medicine , São Paulo , Brazil.
Heart Institute, University of São Paulo School of Medicine , São Paulo , Brazil.
Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo , São Paulo , Brazil.
Molecular Medicine Department, Jichi Medical University , Tochigi , Japan.


Sepsis-induced organ failure is characterized by a massive inflammatory response and oxidative stress. Acute kidney injury (AKI) occurs in approximately half of patients in septic shock, and the mortality associated with sepsis-induced AKI is unacceptably high. Klotho is a protein expressed by renal cells and has anti-senescence properties. Klotho has also been shown to protect the kidneys in ischemia-reperfusion injury and to have antioxidant properties. To analyze the role of Klotho in sepsis-related organ dysfunction and AKI, we used a cecal ligation and puncture (CLP) model of sepsis in heterozygous Klotho-haploinsufficient mice and their wild-type littermates (CLP- Kl/+ and CLP-WT mice, respectively). In comparison with the CLP-WT mice, CLP- Kl/+ mice showed lower survival, impaired renal function, impaired hepatic function, greater oxidative stress, upregulation of inflammatory pathways (at the systemic and kidney tissue levels), and increased NF-κB activation. It is noteworthy that CLP- Kl/+ mice also showed lower heart-rate variability, less sympathetic activity, impaired baroreflex sensitivity to sodium nitroprusside, and a blunted blood pressure response to phenylephrine. We also demonstrated that sepsis creates a state of acute Klotho deficiency. Given that low Klotho expression exacerbates sepsis and multiple organ dysfunction, Klotho might play a protective role in sepsis, especially in elderly individuals in whom Klotho expression is naturally reduced.


Klotho; acute kidney injury; autonomic disorder; multiple organ dysfunction; sepsis

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