Heparanase: A Potential New Factor Involved in the Renal Epithelial Mesenchymal Transition (EMT) Induced by Ischemia/Reperfusion (I/R) Injury

Abstract

BackgroundIschemia/reperfusion (I/R) is an important cause of acute renal failure and delayed graft function, and it may induce chronic renal damage by activating epithelial to mesenchymal transition (EMT) of renal tubular cells. Heparanase (HPSE), an endoglycosidase that regulates FGF-2 and TGFβ-induced EMT, may have an important role. Therefore, aim of this study was to evaluate its role in the I/R-induced renal pro-fibrotic machinery by employing in vitro and in vivo models.MethodsWild type (WT) and HPSE-silenced renal tubular cells were subjected to hypoxia and reoxygenation in the presence or absence of SST0001, an inhibitor of HPSE. In vivo, I/R injury was induced by bilateral clamping of renal arteries for 30 min in transgenic mice over-expressing HPSE (HPA-tg) and in their WT littermates. Mice were sacrificed 48 and 72 h after I/R. Gene and protein EMT markers (α-SMA, VIM and FN) were evaluated by bio-molecular and histological methodologies.ResultsIn vitro: hypoxia/reoxygenation (H/R) significantly increased the expression of EMT-markers in WT, but not in HPSE-silenced tubular cells. Notably, EMT was prevented in WT cells by SST0001 treatment. In vivo: I/R induced a remarkable up-regulation of EMT markers in HPA-tg mice after 48–72 h. Noteworthy, these effects were absent in WT animals.ConclusionsIn conclusion, our results add new insights towards understanding the renal biological mechanisms activated by I/R and they demonstrate, for the first time, that HPSE is a pivotal factor involved in the onset and development of I/R-induced EMT. It is plausible that in future the inhibition of this endoglycosidase may represent a new therapeutic approach to minimize/prevent fibrosis and slow down chronic renal disease progression in native and transplanted kidneys.

Heparanase regulates the M1 polarization of renal macrophages and their crosstalk with renal epithelial tubular cells after ischemia/reperfusion injury

“…As we previously reported, I/R up‐regulates HPSE in tubular cells (21), and here we showed that it modulates the crosstalk between these cells and macrophages by multiple mechanisms, including the induction of apoptosis in tubular epithelial cells after I/R, the production of DAMPs such as HMGB1, and the up‐regulation of TLRs (Fig. 7).…”

“…We have previously reported a greater magnitude of macrophage infiltration 72 h after I/R in mice overexpressing HPSE compared to wild‐type mice (21). HPSE controls the organization and remodeling of the extracellular matrix and is involved in many pathogenic processes, including cancer, inflammation (22–24), kidney disease (25–31), and I/R injury (21). It may also control some of the complex biologic interactions between renal tubular cells and macrophages that have infiltrated into the graft of patients undergoing I/R injury.…”

Inhibition of PTEN Activity Aggravates Post Renal Fibrosis in Mice with Ischemia Reperfusion-Induced Acute Kidney Injury

“…A large amount of evidence indicates that the development of renal fibrosis follows an episode of IR injury [20-22]. To assess the effect of PTEN activity on IR-induced kidney damage, kidney sections were stained with PAS and scored for histological injury 14 days after IR treatment.…”

Forty Years of Basic and Translational Heparanase Research

“…In fact, heparanase research markedly reinforced the significance of the ECM in the control of cell proliferation and differentiation [149][150][151][152]. It led to important and often unexpected observations in diverse normal and pathological processes including, wound healing, angiogenesis [63], autophagy [98], signal transduction [107,156,161], protein trafficking [162], lysosomal secretion [144,163], blood coagulation [92,164], epithelial-mesenchymal transition [165], activation of immune cells [21,[121][122][123], exosome formation [99,100,102], drug resistance [34,166], gene transcription [35,104] and others. While most studies emphasize the involvement of heparanase in cancer progression, other pathologies were investigated.…”