Klotho deficiency aggravates sepsis-related multiple organ dysfunction

Autor(es):Mostrar menos -

Jorge, Lecticia B. ^[1] ; Coelho, Fernanda O. ^[1] ; Sanches, Talita R. ^[1] ; Malheiros, Denise M. A. C. ^[2] ; de Souza, Leandro Ezaquiel ^[3] ; dos Santos, Fernando ^[3] ; Lima, Larissa de Sa ^[4] ; Scavone, Cristoforo ^[4] ; Irigoyen, Maria ^[3] ; Kuro-O, Makoto ^[5] ; Andrade, Lucia ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Div Nephrol, Sch Med, Av Dr Arnaldo 455, Rm 3310, BR-01246903 Sao Paulo - Brazil

^[2] Univ Sao Paulo, Dept Pathol, Sch Med, Sao Paulo - Brazil

^[3] Univ Sao Paulo, Heart Inst, Sch Med, Sao Paulo - Brazil

^[4] Univ Sao Paulo, Dept Pharmacol, Inst Biomed Sci, Sao Paulo - Brazil

^[5] Jichi Med Univ, Mol Med Dept, Shimotsuke, Tochigi - Japan

• Tipo de documento: Artigo Científico
• Fonte: AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY; v. 316, n. 3, p. F438-F448, MAR 2019.
• Citações Web of Science: 0

Resumo

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-KB activation. It is noteworthy that CLP-Kl/+ mice also showed lower heart-rate variability, less sympathetic activity, impaired baroreflex sensitivity to sodium nitroprussidc, 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. (AU)

• Processo FAPESP: 10/19012-0 - Avaliação da terapia com células-tronco hematopoiéticas na doença renal crônica em cães
• Beneficiário: Lucia da Conceição Andrade
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 12/03025-1 - Estudo fisiopatológico dos transportadores urinários ao longo do nefron em camundongos nocaute para gene Klotho: Importância da proteína klotho no transporte tubular, no mecanismos de acidificação e na concentração e diluição urinária
• Beneficiário: Talita Rojas Cunha Sanches
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 10/08529-2 - Deficiência de vitamina D em doentes críticos oncológicos
• Beneficiário: Lucia da Conceição Andrade
• Modalidade de apoio: Auxílio à Pesquisa - Regular