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Endothelin-1 (ET-1) is a peptide hormone that functions as a vasoconstrictor in the vasculature, whereas in the collecting duct of the kidney it exerts blood pressure-lowering effects via natriuretic actions. Aberrant ET-1 signaling is associated with several pathological states including hypertension and chronic kidney disease. ET-1 expression is regulated largely through transcriptional control of the gene that encodes ET-1,  EDN1 . Here we report a long, non-coding RNA (lncRNA) that appears to be antisense to the  EDN1  gene, called  EDN1-AS . Because  EDN1-AS  represents a potential novel mechanism to regulate ET-1 expression, we examined the regulation of  EDN1-AS  expression and action. A putative glucocorticoid receptor response (GR) element upstream of the predicted  EDN1-AS  transcription start site was identified using the ENCODE database and the UCSC genome browser. Two homozygous deletion clones of the element were generated using CRISPR/Cas9. This deletion resulted in a significant increase in the expression of  EDN1-AS , which was associated with increased secretion of ET-1 peptide from HK-2 cells (two-fold increase in KO cells vs. CNTL,  n  = 7,  P  < 0.05). Phenotypic characterization of these CRISPR clones revealed a difference in cell growth rates. Using a standard growth assay, we determined that the KO1 clone exhibited a three-fold increase in growth over 8 days compared to control cells ( n  = 4,  P  < 0.01) and the KO2 clone exhibited a two-fold increase ( n  = 4,  P  < 0.01). These results support a role for  EDN1-AS  as a novel regulatory mechanism of ET-1 expression and cellular proliferation.

EDN1-AS, A Novel Long Non-coding RNA Regulating Endothelin-1 in Human Proximal Tubule Cells