An integrative analysis of renal miRNA- and mRNA-expression signatures in progressive chronic kidney disease [validation cohort]

MicroRNAs (miRNAs) contribute to chronic kidney disease progression via negatively regulating mRNA abundance. However, their association with clinical outcome remains poorly understood. We performed large-scale miRNA and mRNA expression profiling on cryo-cut renal biopsy sections from a discovery (n=43) and a validation (n=29) cohort. In the discovery cohort (GEO Series accession number GSE45980), miRNAs differentiating stable and progressive cases were determined, and putative target mRNAs showing inversely correlated expression profiles were identified. We found a downregulation of 7 miRNAs in the progressive phenotype, and an upregulation of 29 target mRNAs that are involved in inflammatory response, cell-cell-interaction, apoptosis, and intracellular signaling. Reduced expression of miR-206 in progressive disease correlated with the upregulation of the target mRNAs CCL19, CXCL1, IFNAR2, NCK2, PTK2B, PTPRC, RASGRP1, and TNFRSF25, all participating in inflammatory pathways. Progressive cases also showed a lower expression of miR-532-3p and an increased expression of cognate target transcripts MAP3K14, TNFRSF10B/TRAIL-R2, TRADD, and TRAF2, all being involved in apoptosis pathways. In the independent validation cohort (this set of arrays), we confirmed the decreased expression of miR-206 and miR-532-3p, and the inverse correlation of these miRNAs with the expression of 9 of the 12 target genes. The levels of the identified miRNAs and the target mRNAs correlated to histological damage indices. These results suggest the involvement of specific miRNAs and mRNAs in biological pathways associated with the progression of chronic kidney disease. mRNA- and miRNA-profiling was performed in a discovery cohort (n=43) and in a validation cohort (n=29) of renal biopsy samples from human subjects with various proteinuric nephropathies. In the discovery cohort, miRNA-mRNA correlations were identified for those subjects who showed a progressive decline of renal function during follow up. These profiles were reproduced in the validation cohort.