Klotho deficiency aggravates sepsis-related multiple organ dysfunction

Lectícia B. Jorge, Fernanda O. Coelho, Talita R. Sanches, Denise M.A.C. Malheiros, Leandro Ezaquiel De Souza, Fernando Dos Santos, Larissa De Sá Lima, Cristóforo Scavone, Maria Irigoyen, Makoto Kuro-O, Lucia Andrade

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

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 antisenescence 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 wildtype 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.

Original languageEnglish (US)
Pages (from-to)F438-F448
JournalAmerican Journal of Physiology - Renal Physiology
Volume316
Issue number3
DOIs
StatePublished - 2019

Keywords

  • Acute kidney injury
  • Autonomic disorder
  • Klotho
  • Multiple organ dysfunction
  • Sepsis

ASJC Scopus subject areas

  • Physiology
  • Urology

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