Abstract
Renal tubulointerstitial fibrosis is the final common pathway in end-stage renal disease and is characterized by aberrant accumulation of extracellular matrix (ECM) components secreted by myofibroblasts. Tubular type 2 EMT, induced by TGF-β, plays an important role in renal fibrosis, by participating directly or indirectly in myofibroblasts generation. TGF-β1-induced apoptosis and fibrosis in experimental chronic murine kidney diseases are concomitantly associated with an intrarenal decreased expression of the IL-15 survival factor. Since IL-15 counteracts TGF-β1 effects in different cell models, we analyzed whether (1) human chronic inflammatory nephropathies evolving towards fibrosis could be also characterized by a weak intrarenal IL-15 expression and (2) IL-15 could inhibit epithelial-mesenchymal transition (EMT) and excess matrix deposition in human renal proximal tubular epithelial cells (RPTEC). Our data show that different human chronic kidney diseases are characterized by a strong decreased expression of intrarenal IL-15, which is particularly relevant in diabetic nephropathy, in which type 2 tubular EMT plays an important role in fibrosis. Moreover, primary epithelial tubular cultures deprived of growth supplements rapidly produce active TGF-β1 inducing a “spontaneous” EMT process characterized by the loss of membrane-bound IL-15 (mbIL-15) expression. Both “spontaneous” EMT and recombinant human (rh) TGF-β1-induced EMT models can be inhibited by treating RPTEC and HK2 cells with rhIL-15. Through a long-lasting phospho-c-jun activation, IL-15 inhibits rhTGF-β1-induced Snail1 expression, the master inducer of EMT, and blocks TGF-β1-induced tubular EMT and downstream collagen synthesis. In conclusion, our data suggest that intrarenal IL-15 could be a natural inhibitor of TGF-β in human kidney able to guarantee epithelial homeostasis and to prevent EMT process. Thus, both in vivo and in vitro an unbalance in intrarenal IL-15 and TGF-β1 levels could render RPTEC cells more prone to undergo EMT process. Exogenous IL-15 treatment could be beneficial in some human nephropathies such as diabetic nephropathy.
Highlights
Epithelial-to-mesenchymal transition (EMT) is a critical process that occurs both in normal development and in pathological settings, where epithelial cells lose their epithelial nature and gain mesenchymal characteristics [1]
Since intrarenal IL-15 is strongly decreased in several experimental murine nephropathies compromising renal function [20, 21], we have first investigated the IL-15 expression profile for kidney biopsies of transplant patients and of human nephropathies by bioinformatics based on microarray datasets
To confirm at protein level that IL-15 expression is reduced in human inflammatory nephropathies, immunohistochemistry was performed on paraffin-embedded kidney tissues from human renal biopsies
Summary
Epithelial-to-mesenchymal transition (EMT) is a critical process that occurs both in normal development and in pathological settings, where epithelial cells lose their epithelial nature and gain mesenchymal characteristics [1]. Results have conflicted, assigning either an important or a negligible role to tubular type 2 EMT in myofibroblasts generation [9,10,11,12], whose intervention is limited to diabetic nephropathy (DN) [13,14,15]. In this context, a recent study reconciles conflicting data on role of EMT, showing that a partial and reversible tubular EMT, induced by Snail reactivation, relays signals to the interstitium to promote myofibroblast differentiation from cells of renal or extrarenal origin, demonstrating a new role of EMT in renal fibrosis [16]. TGF-β1–induced expression of Twist or Snail induces a partial EMT that leads to G2 arrest of tubular epithelial cells, limiting their potential for repair and regeneration [11]
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