Klotho deficiency aggravates sepsis-related multiple organ dysfunction

Author(s):Show less -

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]

Affiliation

^[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

• Document type: Journal article
• Source: AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY; v. 316, n. 3, p. F438-F448, MAR 2019.
• Web of Science Citations: 0

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 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)

• FAPESP's process: 10/19012-0 - Evaluation of hematopoietic stem cell treatment in dogs with chronic renal failure
• Grantee: Lucia da Conceição Andrade
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 12/03025-1 - Pathophysiological study of urinary transporters along the nephron in mice knockout for Klotho gene: The importance of klotho protein in tubular transport, in the acidification mechanisms and in the urinary dilution and concentration
• Grantee: Talita Rojas Cunha Sanches
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 10/08529-2 - Vitamin D deficiency in oncological critically ill patients
• Grantee: Lucia da Conceição Andrade
• Support Opportunities: Regular Research Grants