title: 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.affiliation: Division of Nephrology, University of São Paulo School of Medicine, São Paulo, Brazil; Heart Institute, University of São Paulo School of Medicine Hospital das Clínicas, São Paulo, Brazil;
authors.forename: Roberto S
authors.initials: RS
authors.lastname: Moreira
authors.affiliation: Heart Institute, University of São Paulo School of Medicine Hospital das Clínicas, São Paulo, Brazil;
authors.forename: Maria
authors.initials: M
authors.lastname: Irigoyen
authors.affiliation: Division of Nephrology, University of São Paulo School of Medicine, São Paulo, Brazil;
authors.forename: Talita R
authors.initials: TR
authors.lastname: Sanches
authors.affiliation: Division of Nephrology, University of São Paulo School of Medicine, São Paulo, Brazil;
authors.forename: Rildo A
authors.initials: RA
authors.lastname: Volpini
authors.affiliation: Immunology Department, University of São Paulo, São Paulo, Brazil; and.
authors.forename: Niels O S
authors.initials: NO
authors.lastname: Camara
authors.affiliation: Department of Pathology, University of São Paulo School of Medicine, São Paulo, Brazil.
authors.forename: Denise M
authors.initials: DM
authors.lastname: Malheiros
authors.affiliation: Division of Nephrology, University of São Paulo School of Medicine, São Paulo, Brazil;
authors.forename: Maria H M
authors.initials: MH
authors.lastname: Shimizu
authors.affiliation: Division of Nephrology, University of São Paulo School of Medicine, São Paulo, Brazil;
authors.forename: Antonio C
authors.initials: AC
authors.lastname: Seguro
authors.affiliation: Division of Nephrology, University of São Paulo School of Medicine, São Paulo, Brazil; luciacan@usp.br.
authors.forename: Lucia
authors.initials: L
authors.lastname: Andrade
mesh_terms: D058186:Acute Kidney Injury / Q000378:metabolism / Q000503:physiopathology* / Q000517:prevention & control*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002463:Cell Membrane Permeability / Q000187:drug effects / Q000502:physiology; D008076:Cholesterol, HDL / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology*; D006335:Heart Injuries / Q000378:metabolism / Q000503:physiopathology* / Q000517:prevention & control*; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D011956:Receptors, Cell Surface / Q000378:metabolism; D018805:Sepsis / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D000098552:Slit Homolog 2 Protein; D000097905:Roundabout Proteins
chemical_list: D008076:Cholesterol, HDL; D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D052250:Nitric Oxide Synthase Type III; D010455:Peptides; D011956:Receptors, Cell Surface; D000098552:Slit Homolog 2 Protein; C578845:Robo4 protein, rat; D000097905:Roundabout Proteins; C582295:apolipoprotein A-I mimetic peptide 4F; C496316:Nos3 protein, rat
keywords: apolipoproteins; cardiac failure; endothelium-derived factors; infection; kidney; nitric oxide synthase