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Antagonism of scavenger receptor CD36 by 5A peptide prevents chronic kidney disease progression in mice independent of blood pressure regulation.

ABSTRACT: Scavenger receptor CD36 participates in lipid metabolism and inflammatory pathways important for cardiovascular disease and chronic kidney disease (CKD). Few pharmacological agents are available to slow the progression of CKD. However, apolipoprotein A-I-mimetic peptide 5A antagonizes CD36 in vitro. To test the efficacy of 5A, and to test the role of CD36 during CKD, we compared wild-type to CD36 knockout mice and wild-type mice treated with 5A, in a progressive CKD model that resembles human disease. Knockout and 5A-treated wild-type mice were protected from CKD progression without changes in blood pressure and had reductions in cardiovascular risk surrogate markers that are associated with CKD. Treatment with 5A did not further protect CD36 knockout mice from CKD progression, implicating CD36 as its main site of action. In a separate model of kidney fibrosis, 5A-treated wild-type mice had less macrophage infiltration and interstitial fibrosis. Peptide 5A exerted anti-inflammatory effects in the kidney and decreased renal expression of inflammasome genes. Thus, CD36 is a new therapeutic target for CKD and its associated cardiovascular risk factors. Peptide 5A may be a promising new agent to slow CKD progression.

SUBMITTER: Souza AC

PROVIDER: S-EPMC4800337 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Antagonism of scavenger receptor CD36 by 5A peptide prevents chronic kidney disease progression in mice independent of blood pressure regulation.

Souza Ana Carolina P AC Bocharov Alexander V AV Baranova Irina N IN Vishnyakova Tatyana G TG Huang Yuning G YG Wilkins Kenneth J KJ Hu Xuzhen X Street Jonathan M JM Alvarez-Prats Alejandro A Mullick Adam E AE Patterson Amy P AP Remaley Alan T AT Eggerman Thomas L TL Yuen Peter S T PS Star Robert A RA

Kidney international 20160401 4

Scavenger receptor CD36 participates in lipid metabolism and inflammatory pathways important for cardiovascular disease and chronic kidney disease (CKD). Few pharmacological agents are available to slow the progression of CKD. However, apolipoprotein A-I-mimetic peptide 5A antagonizes CD36 in vitro. To test the efficacy of 5A, and to test the role of CD36 during CKD, we compared wild-type to CD36 knockout mice and wild-type mice treated with 5A, in a progressive CKD model that resembles human di ...[more]

PMID: 26994575

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Project description:Graphene nanoplatelets (GNPs) are novel two-dimensional engineered nanomaterials consisting of planar stacks of graphene. Although human exposures are increasing, our knowledge is lacking regarding immune-specific responses to GNPs and mechanisms of interactions. Our current study utilizes a metabolite profiling approach to evaluate macrophage responses to GNPs. Furthermore, we assessed the role of the scavenger receptor CD36 in mediating these GNP-induced responses. GNPs were purchased with dimensions of 2 ?m × 2 ?m × 12 nm. Macrophages were exposed to GNPs at different concentrations of 0, 25, 50, or 100 ?g/ml for 1, 3, or 6 h. Following exposure, no cytotoxicity was observed, while GNPs readily associated with macrophages in a concentration-dependent manner. After the 1h-pretreatment of either a CD36 competitive ligand sulfo-N-succinimidyl oleate (SSO) or a CD36 specific antibody, the cellular association of GNPs by macrophages was significantly reduced. GNP exposure was determined to alter mitochondrial membrane potential while the pretreatment with a CD36 antibody inhibited these changes. In a separate exposure, macrophages were exposed to GNPs at concentrations of 0, 50, or 100 ?g/mL for 1 or 3h or 100 ?M SSO (a CD36 specific ligand) for 1h and collected for metabolite profiling. Principal component analysis of identified compounds determined differential grouping based on exposure conditions. The number of compounds changed following exposure was determined to be both concentration- and time-dependent. Identified metabolites were determined to relate to several metabolism pathways such as glutathione metabolism, Pantothenate and CoA biosynthesis, Sphingolipid metabolism, Purine metabolism, arachidonic acid metabolism and others. Lastly, a number of metabolites were found in common between cells exposed to the CD36 receptor ligand, SSO, and GNPs suggesting both CD36-dependent and independent responses to GNP exposure. Together our data demonstrates GNP-macrophage interactions, the role of CD36 in the cellular response, and metabolic pathways disrupted due to exposure.

Dataset Information

Antagonism of scavenger receptor CD36 by 5A peptide prevents chronic kidney disease progression in mice independent of blood pressure regulation.

Publications

Antagonism of scavenger receptor CD36 by 5A peptide prevents chronic kidney disease progression in mice independent of blood pressure regulation.

Similar Datasets

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