Apolipoprotein A-I mimetic peptide 4F attenuates kidney injury, heart injury, and endothelial dysfunction in sepsis.

Abstract

Kidney injury, heart injury, and cytokine-induced vascular hyperpermeability are associated with high rates of morbidity and mortality in sepsis. Although the mechanism remains unknown, apolipoprotein A-I (apoA-I) mimetic peptide 4F reduces inflammation and protects HDL levels, which are reduced in sepsis. We hypothesized that 4F also protects kidneys and hearts in a rat model of cecal ligation and puncture (CLP). We divided Wistar rats into groups: sham-operated (control), CLP, and CLP+4F (10 mg/kg body wt ip, 6 h after CLP). At 24 h post-CLP, we evaluated cardiac function, mean arterial pressure (MAP), heart rate (HR), baroreflex sensitivity, total cholesterol, LDL, HDL, serum cytokines, and inulin clearance. We performed immunoblotting for protein regulators of vascular permeability (Slit2 and Robo4) and endothelial nitric oxide synthase (eNOS) in kidney tissue. We evaluated heart mitochondria with electron microscopy. Although there was no difference in MAP, the HR was significantly higher in CLP rats than in control and CLP+4F rats. In CLP+4F rats, baroreflex sensitivity and cardiac function were completely protected from the effects of CLP, as was glomerular filtration; heart mitochondria morphology was improved; sepsis-induced changes in serum cholesterol, LDL, HDL, and apoA-I were less common; all cytokines were lower than in CLP rats; and expression of Slit2, Robo4, and eNOS was completely restored. Administration of 4F inhibits inflammatory responses and strengthens the vascular barrier, protecting kidneys and hearts in an HDL-dependent manner. To determine the extent of the protective effect of 4F, further studies are needed.

• Authors: Roberto S Moreira, Maria Irigoyen, Talita R Sanches, Rildo A Volpini, Niels O S Camara, Denise M Malheiros, Maria H M Shimizu, Antonio C Seguro, Lucia Andrade
• Journal: American journal of physiology. Regulatory, integrative and comparative physiology (Am J Physiol Regul Integr Comp Physiol) Vol. 307 Issue 5 Pg. R514-24 (Sep 01 2014) ISSN: 1522-1490 [Electronic] United States
• PMID: 24920733 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 the American Physiological Society.

Chemical References

• Cholesterol, HDL
• Cytokines
• Intercellular Signaling Peptides and Proteins
• Nerve Tissue Proteins
• Peptides
• Receptors, Cell Surface
• Robo4 protein, rat
• apolipoprotein A-I mimetic peptide 4F
• Nitric Oxide Synthase Type III
• Nos3 protein, rat
• Slit homolog 2 protein

Topics

• Acute Kidney Injury (metabolism, physiopathology, prevention & control)
• Animals
• Blood Pressure (drug effects, physiology)
• Cell Membrane Permeability (drug effects, physiology)
• Cholesterol, HDL (metabolism)
• Cytokines (metabolism)
• Disease Models, Animal
• Endothelium, Vascular (drug effects, physiopathology)
• Heart Injuries (metabolism, physiopathology, prevention & control)
• Heart Rate (drug effects, physiology)
• Intercellular Signaling Peptides and Proteins (metabolism)
• Male
• Nerve Tissue Proteins (metabolism)
• Nitric Oxide Synthase Type III (metabolism)
• Peptides (pharmacology, therapeutic use)
• Rats
• Rats, Wistar
• Receptors, Cell Surface (metabolism)
• Sepsis (complications, metabolism, physiopathology)