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

Abstract

Heparanase (HPSE) is part of the biologic network triggered by ischemia/reperfusion (I/R) injury, a complication of renal transplantation and acute kidney injury. During this period, the kidney or graft undergoes a process of macrophages recruitment and activation. HPSE may therefore control these biologic effects. We measured the ability of HPSE and its inhibitor, SST0001, to regulate macrophage polarization and the crosstalk between macrophages and HK-2 renal tubular cells during in vitro hypoxia/reoxygenation (H/R). Furthermore, we evaluated in vivo renal inflammation, macrophage polarization, and histologic changes in mice subjected to monolateral I/R and treated with SST0001 for 2 or 7 d. The in vitro experiments showed that HPSE sustained M1 macrophage polarization and modulated apoptosis, the release of damage associated molecular patterns in post-H/R tubular cells, the synthesis of proinflammatory cytokines, and the up-regulation of TLRs on both epithelial cells and macrophages. HPSE also regulated M1 polarization induced by H/R-injured tubular cells and the partial epithelial-mesenchymal transition of these epithelial cells by M1 macrophages. All these effects were prevented by inhibiting HPSE. Furthermore, the inhibition of HPSE in vivo reduced inflammation and M1 polarization in mice undergoing I/R injury, partially restored renal function and normal histology, and reduced apoptosis. These results show for the first time that HPSE regulates macrophage polarization as well as renal damage and repair after I/R. HPSE inhibitors could therefore provide a new pharmacologic approach to minimize acute kidney injury and to prevent the chronic profibrotic damages induced by I/R.-Masola, V., Zaza, G., Bellin, G., Dall'Olmo, L., Granata, S., Vischini, G., Secchi, M. F., Lupo, A., Gambaro, G., Onisto, M. Heparanase regulates the M1 polarization of renal macrophages and their crosstalk with renal epithelial tubular cells after ischemia/reperfusion injury.

Circular RNA YAP1 acts as the sponge of microRNA‐21‐5p to secure HK‐2 cells from ischaemia/reperfusion‐induced injury

“…I/R injury is derived from inadequate supplement of oxygen and nutrient to organs or accumulation of metabolic waste products, and then gradually evolved into structural modification of tubular epithelial cells and immunocytes . It was demonstrated by several researchers that a multitude of inflammatory responses, including secretion of inflammatory cytokines, cell apoptosis and necrocytosis, were triggered by I/R stimulation in HK‐2 cells . As previously reported, our research manifested that I/R exposure impeded cell viability and expedited cell apoptotic capacity of HK‐2 cells.…”

Tissue talks: immunophenotype of cells infiltrating the graft explains histological findings and the benefits of belatacept at 10 years

“…These elements of innate immune system play key roles in tissue injury, not only by producing a variety of proinflammatory cytokines but also via proteolytic enzymes or promotion of the immune response by presenting antigens to lymphocytes in ischemia-reperfusion injury, impacting early and late graft dysfunction. Interestingly, M1 monocytes have been shown to have altered activation levels, exhibited by enhanced TNF-α production in patients undergoing chronic renal rejection [21,35,36]. In the present study, we found lower relative percentages of M1 cells in patients under belatacept treatment than in those under CNI treatment.…”

“…Interestingly, M1 monocytes have been shown to have altered activation levels, exhibited by enhanced TNF-α production in patients undergoing chronic renal rejection [21,35,36]. These elements of innate immune system play key roles in tissue injury, not only by producing a variety of proinflammatory cytokines but also via proteolytic enzymes or promotion of the immune response by presenting antigens to lymphocytes in ischemia-reperfusion injury, impacting early and late graft dysfunction.…”

Heparanase: A Multitasking Protein Involved in Extarcellular Matrix (ECM) Remodeling and Cellular Signaling

“…Recently, it has been proved that HPSE regulates macrophage polarization and the crosstalk between macrophages and proximal tubular epithelial cells after ischemia/reperfusion (I/R) injury [34]. In particular, I/R injury up-regulates HPSE at both tubular and glomerular levels.…”

“…DAMPs, HPSE-released HS-fragments and molecules generated from necrotic cells activate TLRs both on macrophages and tubular cells. Tubular cells in response to direct hypoxic stimuli and TLR activation produce pro-inflammatory cytokines which attract and activate macrophages and the presence of high levels of HPSE facilitates M1 polarization of infiltrated macrophages which worsen parenchymal damage [34].…”