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Abrogation by Growth Hormone of Homocysteine‐Induced Epithelial‐to‐Mesenchymal Transition through Lipid Raft Redox Signaling in Podocytes
Author(s) -
Li Caixia,
Xia Min,
Han Weiqing,
Li Xiaoxue,
Zhang Chun,
Li PinLan
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.665.22
Subject(s) - podocyte , slit diaphragm , podocin , endocrinology , medicine , nephrin , chemistry , microbiology and biotechnology , biology , kidney , proteinuria
Growth hormone (GH) perturbations have been reported to importantly contribute to the development of different chronic degenerative diseases. The present study was designed to test a hypothesis that GH abrogates homocysteine (Hcys)‐induced Epithelial‐to‐Mesenchymal Transition (EMT) in podocytes and thereby protects the kidney from Hcys‐induced glomerular sclerosis. By fluorescent immunocytochemical examinations, we found that Hcys induced significant EMT in podocytes, as shown by marked decreases in slit diaphragm‐associated protein P‐cadherin and zonula occludens‐1 (ZO‐1) as epithelial marker and by dramatic increases in the expression of mesenchymal markers, fibroblast specific protein‐1 (FSP‐1) and α‐smooth muscle actin (α‐SMA). When these podocytes were treated with GH at 25 ng/ml, EMT of these cells was substantially blocked. Western blot analysis also demonstrated similar effect of GH on Hcys‐induced changes in expression of podocytes epithelial and mesenchymal markers. Using electromagnetic spin resonance spectrometry, it was found that Hcys‐induced superoxide (O 2 .− ) production via NADPH oxidase was significantly inhibited by GH (66%). Functionally, GH was found to almost completely inhibit Hcys‐induced increases in the permeability of podocyte monolayer. Hcys‐enhanced podocin expression in these podocytes was also significantly suppressed. Further, confocal microscopy showed that gp91 phox and GH receptors could be aggregated in lipid raft (LR) clusters in podocyte membrane to produce O 2 •− in response to Hcys. This Hcys‐induced LR clustering and O 2 •− production were blocked by GH or filipin, a LR disrupter. It is concluded that GH exerts beneficial action to improve Hcys‐induced podocyte injury by abrogation of EMT associated with LR redox signaling (supported by NIH grants HL 57244, DK54927).