HSP47 regulates ECM accumulation in renal proximal tubular cells induced by TGF-β₁through ERK1/2 and JNK MAPK pathways

Abstract

Heat shock protein (HSP)47 is a collagen-specific molecular chaperone that is essential for the biosynthesis of collagen molecules. It is likely that increased levels of HSP47 contribute to the assembly of procollagen and thereby cause an excessive accumulation of collagens in disease processes associated with fibrosis. Although HSP47 promotes renal fibrosis, the underlying mechanism and associated signaling events have not been clearly delineated. We examined the role of HSP47 in renal fibrosis using a rat unilateral ureteral obstruction model and transforming growth factor (TGF)-β(1)-treated human proximal tubular epithelial (HK-2) cells. An upregulation of HSP47 in both in vivo and in vitro models was observed, which correlated with the increased synthesis of extracellular matrix (ECM) proteins and expression of tissue-type plasminogen activator inhibitor (PAI)-1. Blockade of HSP47 by short interfering RNA suppressed the expression of ECM proteins and PAI-1. In addition, TGF-β(1)-induced HSP47 expression in HK-2 cells was attenuated by ERK1/2 and JNK MAPK inhibitors. These data suggest that ERK1/2 and JNK signaling events are involved in modulating the expression of HSP47, the chaperoning effect of which on TGF-β(1) would ultimately contribute to renal fibrosis by enhancing the synthesis and deposition of ECM proteins.

Heat shock proteins and kidney disease: perspectives of HSP therapy

“…HSP47 may be involved in the initial stage of fibrosis via the TGF-β1induced transdifferentiation of fibroblasts to myofibroblasts, as well as at the later stage of fibrosis, the collagen synthesis in already transdifferentiated myofibroblasts (Hong et al 2012). HSP47 increases the expression of collagen type I, collagen type IV, fibronectin, and tissue-type plasminogen activator inhibitor in human proximal tubular epithelial (HK-2) cells, suggesting the functionality of HSP47 in regulating ECM synthesis and degradation in processes related to renal tubulointerstitial fibrosis (Xiao et al 2012).…”

The study on serum and urine of renal interstitial fibrosis rats induced by unilateral ureteral obstruction based on metabonomics and network analysis methods

“…RIF is caused by the loss of normal renal units, the proliferation of fibroblasts and myofibroblasts, and the production and accumulation of extracellular matrix [2]. Recent studies have indicated that the progression of RIF involves various molecular signaling pathways, such as TGF-β/Smad [3], p38 MAPK [4], extracellular signal regulated kinase 1/2, and cJun N-terminal kinase [5]. For decades, considerable efforts have been devoted to studying the pathogenesis of RIF, but its molecular mechanism remains unresolved to date [6].…”

Role of HSP60 (HSPD1) in diabetes‐induced renal tubular dysfunction: regulation of intracellular protein aggregation, ATP production, and oxidative stress

“…8), consistent with the findings from our network prediction. Indeed, some other HSPs, such as HSP47, HSP70, and HSP90, but not HSP60, have been reported to play important roles in ECM protein regulation (47–49). These data indicate that HSP60 may have no significant role in ECM homeostasis (as shown in our study, fibronectin).…”