Regulation of chromogranin A by hsa-miR-107 in hypertension and nephropathy (1136.19)

Chromogranin A (CHGA) is a major protein in secretory vesicles of neuroendocrine cells, co‐released with catecholamines. Genetic variation in the CHGA 3’‐UTR region is associated with hypertensive nephropathy. This study documents the biological mechanism underlying the genetic association of marker and trait. Methods and Results: An African‐American population case/control study showed that individuals carrying the CHGA 3’‐UTR variant C+87T (rs7610) haplotype are likely to develop end stage renal disease. Computational analysis showed that the variant is in a micro‐RNA (hsa‐miR‐107) recognition motif, with a superior match for the risk (T) allele. In vitro expression studies revealed that CHGA mRNA expression is inversely dependent on miR‐107 abundance in cells and tissues. The effects of miR‐107 were seen with transfected chimeric luciferase/CHGA 3’‐UTR (C+87 versus +87T) reporters in cell lines and corroborated in studies of coupled in vitro transcription/translation of each 3’‐UTR/C+87T allele in CHGA cDNA. In vivo, we exploited mice with a “humanized”CHGA locus (T/T homozygotes) generated by BAC transgenesis. These mice treated with miR‐107 antagomir yielded prolonged, significant falls in SBP/DBP compared to the wild‐type mice. Conclusion: The 3’‐UTRmRNA:miRNA‐107 (cis:trans) interaction plays a role in the clinical manifestations of the CHGA 3’‐UTR associations with BP and nephropathy. Grant Funding Source : Supported by National Institutes of Health (SMV & DTO'C)