Association of Elevated Urinary miR-126, miR-155, and miR-29b with Diabetic Kidney Disease

作者：Beltrami Cristina; Simpson Kate; Jesky Mark; Wonnacott Alexa; Carrington Christopher; Holmans Peter; Newbury Lucy; Jenkins Robert; Ashdown Thomas; Dayan Colin; Satchell Simon; Corish Peter; Cockwell Paul; Fraser Donald; Bowen Timothy^*

来源：American Journal Of Pathology, 2018, 188(9): 1982-1992.

DOI：10.1016/j.ajpath.2018.06.006

Effective diabetic kidney disease (DKD) biomarkers remain elusive, and urinary miRNAs represent a potential source of novel noninvasive disease sentinels. We profiled 754 miRNAs in pooled urine samples from DKD patients (n = 20), detecting significantly increased miR-126, miR-155, and miR-29b compared with controls (n = 20). These results were confirmed in an independent cohort of 89 DKD patients, 62 diabetic patients without DKD, and 41 controls: miR-126 (2.8-fold increase; P < 0.0001), miR-155 (1.8-fold increase; P < 0.001), and miR-29b (4.6-fold increase; P = 0.024). Combined receiver operating characteristic curve analysis resulted in an area under the curve of 0.8. A relative quantification threshold equivalent to 80% sensitivity for each miRNA gave a positive signal for 48% of DKD patients compared with 3.6% of diabetic patients without DKD. Laser-capture microdissection of renal biopsy specimens, followed by quantitative RT-PCR, detected miR-155 in glomeruli and proximal and distal tubules, whereas miR-126 and miR-29b were most abundant in glomerular extracts. Subsequent experiments showed miR-126 and miR-29b enrichment in glomerular endothelial cells (GEnCs) compared with podocytes, proximal tubular epithelial cells, and fibroblasts. Significantly increased miR-126 and miR-29b were detected in GEnC conditioned medium in response to tumor necrosis factor-alpha and transforming growth factor-beta 1, respectively. Our data reveal an altered urinary miRNA profile associated with DKD and link these variations to miRNA release from GEnCs.

• 出版日期2018-9