MiR-223 downregulation promotes glomerular endothelial cell activation by upregulating importin α4 and α5 in IgA nephropathy

Abstract

Glomerular endothelial cells (GEnCs) contribute to renal injuries in IgA nephropathy (IgAN). Here we profiled microRNAs (miRNAs) in GEnCs treated with conditioned medium from human mesangial cells in vitro. Levels of miR-223 in GEnCs decreased after incubation with the medium prepared with pIgA from patients with glomerular endothelial proliferation and were also decreased in the glomerular tissues of patients with glomerular endothelial proliferation. Mesangial-derived IL-6 caused miR-223 levels to decrease. The addition of exogenous miR-223 inhibited cell proliferation, ICAM-1 expression, and monocyte adhesion. The NF-κB and STAT3 signaling pathways collaborate during the activation process. MiR-223 mimics inhibited the nuclear localization and DNA binding of p65 and STAT3 but had no effect on the expression of upstream molecules. Instead, importin α4 and α5 (multipurpose nuclear transport receptors), validated as targets of miR-223, were responsible for the nuclear transport of p65 and STAT3. Importin α4 and α5 siRNA inhibited the nuclear localization of p65 and STAT3 and prevented cell proliferation and monocyte adhesion. The level of miR-223 in circulating endothelial cells was decreased and related to the clinical and pathological parameters. Thus, miR-223 downregulation promotes glomerular endothelial cell activation by upregulating importin α4 and α5 in IgAN. Monitoring the level of miR-223 in circulating endothelial cells may provide a noninvasive method for evaluating the severity of IgAN.

Biomarkers in IGA Nephropathy

“…This miRNA is promising as it is only specific in cells treated with medium prepared future science group Review Hwang, Ulu, van Hoorebeke & Weiss from patients with EP and pIgA. However, no change in miR-223 expression was found in GEnCs treated with IgA-HMC medium prepared with pIgA from patients without EP and thus miR-223 may be a better biomarker for EP in general rather than for IgAN [49].…”

“…Bao et al profiled miRNAs in cultured glomerular endothelial cells (GEnCs) treated with conditioned medium from human mesangial cells (HMC) prepared with polymeric IgA (pIgA) from patients with glomerular endothelial proliferation (EP) [49]. They found decreased expression of miR-223 when compared with cells treated with IgA-HMC medium prepared with pIgA from patients without EP or the medium prepared with monomeric IgA from any source.…”

Diagnosis and monitoring of IgA nephropathy: the role of biomarkers as an alternative to renal biopsy

“…Interestingly, the potential of some miRNAs in urine as novel biomarkers for diagnosis and monitoring of IgAN has been documented [15,16,94,95,97]. Intrarenal and urinary levels of miR-146a and miR-155 of IgAN patients are significantly higher than in healthy controls.…”

“…ACCEPTED MANUSCRIPT 16 Moreover, miR-223 expression in glomerular endothelial cells has been associated with glomerular endothelial cell activation and has been proposed as a noninvasive marker for evaluating the severity of IgAN [97].…”

“…IgAN [15,94,95,97]. The quantification of miRNAs might be performed from the and microarray methodologies [15,16].…”