Abstract
Aims To investigate whether bone marrow derived mesenchymal stromal cells (BMSC) have ameliorated ischemia/reperfusion injury-induced acute kidney injury (IRI-AKI) via tumor necrosis factor-inducible gene 6 protein (TSG-6) and how TSG-6 exerted this effect. Methods We used lentiviral vectors of short hairpin RNA (shRNA) targeting TSG-6 gene to silence TSG-6 in BMSC. And TSG-6-silenced BMSC were administrated into IRI-AKI rats. Then we analyzed serum creatinine (Scr) and renal histology of IRI-AKI rats treated with BMSC after different pretreatments. Furthermore, we explored the effect of TSG-6 on renal tubular epithelial cells proliferation in vivo and in vitro assays. Results The Scr levels of IRI-AKI rats treated with BMSC (73.5±7.8 μmol/L) significantly decreased compared to those of IRI-AKI rats treated without BMSC (392.5±24.8 μmol/L, P<0.05) or with DMEM (314.0±19.8 μmol/L, P<0.05). Meanwhile, the renal tissue injury in IRI-AKI rats treated with BMSC improved markedly. However, the Scr levels of IRI-AKI rats treated with TSG-6-silenced BMSC (265.1±21.2 μmol/L) significantly increased compared to those with BMSC (74.0±8.5 μmol/L, P<0.05). The proportion of Ki67-positive cells was reduced in IRI-AKI rats treated with TSG-6-silenced BMSC compared to that in IRI-AKI rats treated with BMSC (29.7±0.8% versus 43.4±3.0%, P<0.05). In vitro, the cell proliferation rate of TSG-6-stimulated NRK-52E cells under hypoxia (89.2±3.9%) increased significantly compared to that of NRK-52E cells alone under hypoxia (82.4±0.8%, P<0.05). Similarly, the proportion of Ki67-positive cells was significantly elevated in TSG-6-stimulated NRK-52E cells under hypoxia. Furthermore, TSG-6 could inhibit infiltration of neutrophils in kidney tissue of IRI-AKI. Conclusions TSG-6 plays a key role in the treatment of IRI-AKI with BMSC, which may be due to its effect on promoting renal tubular epithelial cells proliferation by modulating inflammation.
Highlights
Acute kidney injury (AKI) is a common clinical syndrome characterized by renal dysfunction, which is caused by a spectrum of etiologies in multiple settings
In the damaged microenvironment, activated mesenchymal stromal cells (MSC) can secrete a variety of anti-inflammatory factors to promote tissue repair, including tumor necrosis factor-inducible gene 6 protein (TSG-6), prostaglandin E2, and interleukin-1 receptor antagonist [7]
The proportion of Ki67-positive cells decreased significantly in injury-induced acute kidney injury (IRI-AKI) rats treated with TSG-6-silenced bone marrow derived mesenchymal stromal cells (BMSC) compared to that in ischemia/reperfusion injury (IRI)-AKI rats treated with BMSC (29.7±0.8% versus 43.4±3.0%, P
Summary
Acute kidney injury (AKI) is a common clinical syndrome characterized by renal dysfunction, which is caused by a spectrum of etiologies in multiple settings. Experimental studies have shown that mesenchymal stromal cells (MSC) can promote AKI repair [5]. Several studies have suggested that MSC exert their effect on AKI via the paracrine mechanism [6]. In the damaged microenvironment, activated MSC can secrete a variety of anti-inflammatory factors to promote tissue repair, including tumor necrosis factor-inducible gene 6 protein (TSG-6), prostaglandin E2, and interleukin-1 receptor antagonist [7]. There are very few studies on the effect of TSG6 secreted by MSC in AKI. In view of TSG-6 as a protective inflammatory response gene, we hypothesized that bone marrow derived MSC (BMSC) might exert their therapeutic effect by secreting TSG-6 in AKI. Our results verified that TSG-6 was the key factor that allowed BMSC to treat IRI-AKI and we discussed its possible mechanism
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