Abstract
Tubulointerstitial fibrosis is a major pathological hallmark of diabetic nephropathy. Increasing evidence has shown that epithelial-to-mesenchymal transition (EMT) of renal proximal tubular cells plays a crucial role in tubulointerstitial fibrosis. Herein, we aimed to elucidate the detailed mechanism of EMT in renal tubular cells under high glucose (HG) conditions, and to investigate the potential of licorice, a medicinal herb, to inhibit HG-induced EMT. Our results showed that renal tubular epithelial cells (normal rat kidney cell clone 52E; NRK-52E) exposed to HG resulted in EMT induction characterized by increased fibronectin and α-SMA (alpha-smooth muscle actin) but decreased E-cadherin. Elevated levels of cleaved Notch2, MAML-1 (mastermind-like transcriptional coactivator 1), nicastrin, Jagged-1 and Delta-like 1 were also concomitantly detected in HG-cultured cells. Importantly, pharmacological inhibition, small interfering RNA (siRNA)-mediated depletion or overexpression of the key components of Notch2 signaling in NRK-52E cells supported that the activated Notch2 pathway is essential for tubular EMT. Moreover, we found that licorice extract (LE) with or without glycyrrhizin, one of bioactive components in licorice, effectively blocked HG-triggered EMT in NRK-52E cells, mainly through suppressing the Notch2 pathway. Our findings therefore suggest that Notch2-mediated renal tubular EMT could be a therapeutic target in diabetic nephropathy, and both LE and de-glycyrrhizinated LE could have therapeutic potential to attenuate renal tubular EMT and fibrosis.
Highlights
Diabetic nephropathy (DN) is the leading cause of end stage renal disease (ESRD) [1]
We aimed to examine the role of the Notch signaling pathway in epithelial-to-mesenchymal transition (EMT) induction of renal tubular epithelial cells under high glucose (HG) conditions, and to investigate the potential benefits of licorice extract (LE) and de-glycyrrhizinated LE in preventing HG-induced tubular EMT
(normal rat kidney cell clone 52E) cells as an in vitro model system, we demonstrated that HG treatment induced EMT via activation of the Notch2 signaling pathway
Summary
Diabetic nephropathy (DN) is the leading cause of end stage renal disease (ESRD) [1]. Multiple studies have implicated that myofibroblasts in renal tubulointerstitial fibrosis could derive from a variety of sources including resident fibroblasts, pericytes, circulating hematopoietic or mesenchymal stem cells from bone marrow, endothelial cells, and proximal tubular epithelial cells [4,5]. There are controversies about the origins of myofibroblasts in renal tubulointerstitial fibrosis, renal tubular epithelial cell injury is generally recognized as the key contributor to renal fibrosis [4,5]. Despite the fact that several signaling mediators (such as transforming growth factor β/Smads, interleukins, hypoxia-induced factor 1, Twist and Snail) are implicated in driving EMT of renal tubular epithelial cells [3,9,10,11], the detailed molecular mechanism of renal tubular EMT under diabetic milieu has not been fully determined
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