miR-214 ameliorates acute kidney injury via targeting DKK3 and activating of Wnt/β-catenin signaling pathway

Abstract

BackgroundmiR-214 was demonstrated to be upregulated in models of renal disease and promoted fibrosis in renal injury independent of TGF-β signaling in vivo. However, the detailed role of miR-214 in acute kidney injury (AKI) and its underlying mechanism are still largely unknown.MethodsIn this study, an I/R-induced rat AKI model and a hypoxia-induced NRK-52E cell model were used to study AKI. The concentrations of kidney injury markers serum creatinine, blood urea nitrogen, and kidney injury molecule-1 were measured. The expressions of miR-214, tumor necrosis factor-α, interleukin (IL)-1β, IL-6, were detected by RT-qPCR. The protein levels of Bcl-2, Bax, Dickkopf-related protein 3, β-catenin, c-myc, and cyclinD1 were determined by western blot. Cell apoptosis and caspase 3 activity were evaluated by flow cytometry analysis and caspase 3 activity assay, respectively. Luciferase reporter assay was used to confirm the interaction between miR-214 and Dkk3.ResultsmiR-214 expression was induced in ischemia–reperfusion (I/R)-induced AKI rat and hypoxic incubation of NRK-52E cells. Overexpression of miR-214 alleviated hypoxia-induced NRK-52E cell apoptosis while inhibition of miR-214 expression exerted the opposite effect. Dkk3 was identified as a target of miR-214. Anti-miR-214 abolished the inhibitory effects of DKK3 knockdown on hypoxia-induced NRK-52E cell apoptosis by inactivation of Wnt/β-catenin signaling. Moreover, miR-214 ameliorated AKI in vivo by inhibiting apoptosis and fibrosis through targeting Dkk3 and activating Wnt/β-catenin pathway.ConclusionmiR-214 ameliorates AKI by inhibiting apoptosis through targeting Dkk3 and activating Wnt/β-catenin signaling pathway, offering the possibility of miR-214 in the therapy of ischemic AKI.Electronic supplementary materialThe online version of this article (10.1186/s40659-018-0179-2) contains supplementary material, which is available to authorized users.

Interstitial microRNA miR-214 attenuates inflammation and polycystic kidney disease progression

“…In this regard, an obvious but challenging question moving forward is whether drugs such as miRNA mimics designed to further enhance miR-214 activity are beneficial in ADPKD. Similar to our findings, miR-214 expression is increased in mouse models of acute kidney injury and fibrosis (34)(35)(36). However, miR-214 appears to produce divergent effects in kidney injury models.…”

“…However, miR-214 appears to produce divergent effects in kidney injury models. Whereas in mouse models, miR-214 deletion is beneficial, in a rat model of kidney injury, miR-214 inhibition is reported to be detrimental (35). Finally, our work provides new insights into inflammation signaling in ADPKD.…”

DKK3 attenuates JNK and AP-1 induced inflammation via Kremen-1 and DVL-1 in mice following intracerebral hemorrhage

“…A reduction in inflammatory infiltrates is associated with an attenuation of brain injury of ICH [36][37][38]. Previously, DKK3 was observed at high levels in the liver, heart, kidney, and brain [39][40][41][42]. DKK3 overexpression substantially alleviated cardiac hypertrophy and fibrosis [10].…”

DKK3 attenuates JNK and AP-1 induced inflammation via Kremen-1 and DVL-1 in mice following intracerebral hemorrhage

“…A reduction in inflammatory infiltrates is associated with an attenuation of brain injury of ICH (32)(33)(34). Previously, DKK3 was observed at high levels in the liver, heart, kidney and brain (35)(36)(37)(38). DKK3 overexpression substantially alleviated cardiac hypertrophy and fibrosis (10).…”