Abstract 13004: Fractalkine Promotes the Progression of Diabetes-Induced Cardiorenal Syndrome through Induction of Mitochondrial Dysfunction and Cell Apoptosis
Background: The prognosis of diabetes mellitus (DM)-induced cardiorenal syndrome (CRS) is poor and its pathogenesis remains elusive. We have reported that chemokine fractalkine (FKN) exacerbated heart failure via promotion of cardiomyocytes (CMs) apoptosis. Moreover, emerging evidence supports that FKN is also involved in renal impairment and mitochondrial dysfunction plays critical role in cell injury. Accordingly, we hypothesized that FKN would be an important factor to promote cardiorenal dysfunction in DM-induced CRS by worsening mitochondria dysfunction.
Methods and Results: Exposure of cultured CMs or glomerular mesangial cells (GMCs) to high concentrations of glucose resulted in an increase of FKN expression. FKN expressions were also significant enhanced in the tissues of heart and kidney in DM mice induced by streptozotocin (STZ). In CMs and GMCs soluble FKN 200ng/ml directly activated RhoA GTPase and up-regulated the expression of ROCK1. FKN significantly induced Bax translocation to the mitochondria, enhancement of mitochondrial permeability transition measured by calcium plus CoCl2 assay, decrease in mitochondrial membrane potential analyzed by TMRE, release of cytochrome C and apoptosis-inducing factor from the mitochondria into the cytosol, activation of caspase-9 and increase terminal DNA fragmentation. These effects of FKN were inhibited by concurrent treatment with either CX3CR1 (FKN receptor) neutralizing antibody or Rho kinase inhibitor Y-27632.Furthermore, RNA interference targeted CX3CR1 diminished apoptotic cell death induced by high glucose. In STZ-induced DM model, CX3CR1 deficiency mice showed less apoptotic cells, ameliorated mitochondria damage and preserved cardiac (higher left ventricular fractional shortening) and renal(lower lipocalin expression and serum creatinine) function in contrast to the wild type littermates.
Conclusion: The present study demonstrates for the first time that FKN accelerates the mitochondrial apoptotic pathway through activation of RhoA/ROCK1-Bax signaling. The proapoptotic effect of FKN may directly contribute to the progression of CRS induced by DM. Inhibition of FKN/CX3CR1 may represent a novel therapeutic strategy for ameliorating DM-induced CRS.
- © 2012 by American Heart Association, Inc.