Heparanase is a key player in renal fibrosis by regulating TGF-β expression and activity

Abstract

Epithelial-mesenchymal transition (EMT) of tubular cells is one of the mechanisms which contribute to renal fibrosis and transforming growth factor-β (TGF-β) is one of the main triggers. Heparanase (HPSE) is an endo-β-D-glucuronidase that cleaves heparan-sulfate thus regulating the bioavailability of growth factors (FGF-2, TGF-β). HPSE controls FGF-2-induced EMT in tubular cells and is necessary for the development of diabetic nephropathy in mice. The aim of this study was to investigate whether HPSE can modulate the expression and the effects of TGF-β in tubular cells. First we proved that the lack of HPSE or its inhibition prevents the increased synthesis of TGF-β by tubular cells in response to pro-fibrotic stimuli such as FGF-2, advanced glycosylation end products (AGE) and albumin overload. Second, since TGF-β may derive from sources different from tubular cells, we investigated whether HPSE modulates tubular cell response to exogenous TGF-β. HPSE does not prevent EMT induced by TGF-β although it slows its onset; indeed in HPSE-silenced cells the acquisition of a mesenchymal phenotype does not develop as quickly as in wt cells. Additionally, TGF-β induces an autocrine loop to sustain its signal, whereas the lack of HPSE partially interferes with this autocrine loop. Overall these data confirm that HPSE is a key player in renal fibrosis since it interacts with the regulation and the effects of TGF-β. HPSE is needed for pathological TGF-β overexpression in response to pro-fibrotic factors. Furthermore, HPSE modulates TGF-β-induced EMT: the lack of HPSE delays tubular cell transdifferentiation, and impairs the TGF-β autocrine loop.

Involvement of heparanase in the pathogenesis of acute kidney injury: nephroprotective effect of PG545

“…Upregulation of the TGF-β gene suggests that I/R triggers renal fibrogenesis, most likely through epithelial-mesenchimal transition (EMT) of tubular cells [48]. Hparanase seems to play a major role in these processes as was evident by the exaggerated overexpression of TGF-β in Hpa-tg mice exposed to I/R.…”

Impact of heparanase on renal fibrosis

“…Nevertheless, HPSE triggers a number of signaling pathways by: (1) digesting HS chains and causing the release of growth factors and cytokines bound to HS, thereby regulating their free levels in the pericellular microenvironment; (2) interacting via its C-terminal domain [22], with several transmembrane heparanase-binding proteins (HBP) and activating kinases such as Src, Akt, and p38 MAPK; (3) modulating the activity of the FGF-2 and TGF-β signaling cascades [23, 24] and (4) converting the soluble HS fragments of SDC1 from inhibitors into potent activators of FGF-2 signaling [25]. …”

“…Additionally, a lack of HPSE delays the onset of EMT induced by TGF-β and hampers the autocrine loop induced by TGF-β [24]. …”

“…In tubular cells, HPSE inhibition prevents the HS degradation induced by pro-fibrotic factors [31], EMT induced by FGF-2 [23, 51], and TGF-β upregulation after treatment with pro-fibrotic factors [24]. In animal models, a beneficial effect on the onset and development of diabetic nephropathy, and on the renal overexpression of TGF-β has been obtained with heparin-derived drugs [53], and sulodexide [54].…”

You-gui Pill ameliorates renal tubulointerstitial fibrosis via inhibition of TGF-β/Smad signaling pathway

“…From our result, histopathological scores, inflammatory cells count and renal interstitial expansion increased significantly in UUO kidneys, whereas YGW treatment decreased The infiltrating inflammatory cell produces a variety of proinflammatory cytokines, including TGF-β. TGF-β is elevated in various experimental and human kidney diseases relating with glomerular and interstitial fibrosis, such as diabetic nephropathy (Masola et al, 2014;Zhou et al, 2014), rat models of obstructive kidney disease (Chevalier, 2006;Kumpers et al, 2007), renal ischemia-reperfusion injury and five-sixths nephrectomy (Tu et al, 2008;Wen et al, 2010). It has been widely accepted that TGF-β1, the major isoform of the TGF-β superfamily, is produced by fibroblasts under various pathophysiological conditions.…”