miR-34c-5p and CaMKII are involved in aldosterone-induced fibrosis in kidney collecting duct cells

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Abstract

Mineralocorticoids trigger a profibrotic process in the kidney. In mouse cortical collecting duct cells, the present study addressed two main questions: 1) what are microRNAs (miRNAs) and their target genes that are changed by aldosterone? and 2) what do miRNAs, in response to aldosterone, regulate regarding signaling pathways related to fibrosis? A mi-croarray chip assay was done in cells in the absence or presence of aldosterone treatment (10+6 M; 3 days). The candidate miRNAs were identified by the criteria of >30% of fold change among the significantly changed miRNAs (P < 0.05). Twenty-nine miRNAs were upregulated (>1.3-fold), and 27 miRNAs were downregulated (<0.7-fold). Putative target genes of identified miRNAs were associated with 74 Kyoto Encyclopedia of Genes and Genomes pathways. Among them, the wingless-related integration site (Wnt) signaling pathway was highly ranked, where 15 mature miRNAs were observed. These miRNAs were further analyzed by real-time quantitative PCR, and among them, miR-130b-3p, miR-34c-5p, and miR-146a-5p were selected. Through the identification of putative target genes of these three miRNAs, mRNA and protein expression of the Ca2+/calmodulin-dependent protein kinase type II β-chain (Camk2b) gene (a target gene of miR-34c-5p) were found to be increased significantly in aldosterone-treated cells, where fibronectin (FN) and α-smooth muscle actin were induced. When CaMKIIβ small interfering RNA or the miR-34c-5p mimic was transfected, aldosterone-induced FN expression was significantly attenuated, along with reduced CaMKIIβ protein expression. A luciferase reporter assay revealed a decrease of CaMKIIβ translation in cells transfected with miRNA mimics of miR-34c-5p. In conclusion, aldosterone-induced downregulation of miR-34c-5p in the Wnt signaling pathway and a consequent increase of CaMKIIβ expression are likely to be involved in aldosterone-induced fibrosis.

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Park, E. J., Jung, H. J., Choi, H. J., Cho, J. I., Park, H. J., & Kwon, T. H. (2018). miR-34c-5p and CaMKII are involved in aldosterone-induced fibrosis in kidney collecting duct cells. American Journal of Physiology - Renal Physiology, 314(3), F329–F342. https://doi.org/10.1152/ajprenal.00358.2017

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