Author:
Dihazi Hassan,Dihazi Gry Helene,Bibi Asima,Eltoweissy Marwa,Mueller Claudia A.,Asif Abdul R.,Rubel Diana,Vasko Radovan,Mueller Gerhard A.
Abstract
Renal fibrosis is characterized by excessive accumulation of extracellular matrix (ECM), which compromises organ function by replacing normal organ tissue. The molecular mechanisms leading to renal fibrosis are not fully understood. Here we demonstrated that TGFß1, AgII or PDGF stimulation of renal cells resulted in ER-stress followed by activation of the protective unfolded protein response pathway and high secretory level of protein disulfide isomerase ERP57. The TGFß1 impairment of ER-function could be reversed by BMP7 treatment suggesting a specific involvement in renal fibrosis. Clear correlation between the degree of fibrosis, ER-stress and ERP57 level could be evidenced in fibrosis animal models and in biopsies of renal fibrosis patient's. Protein interaction studies revealed that secreted ERP57 exhibit a strong interaction with ECM proteins. Knockdown of ERP57 or antibody targeted inhibition of the secreted form impaired significantly the secretion and accumulation of ECM. Moreover ERP57 was excreted in earlier stage of chronic kidney diseases and its level in urine correlated with the degree of renal fibrosis suggesting that the ERP57 secretion may represent one of the first signs of renal fibrosis onset and progression.
Publisher
The Company of Biologists
Cited by
59 articles.
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