Molecular Mechanism for Hypertensive Renal Disease: Differential Regulation of Chromogranin A Expression at 3'-Untranslated Region Polymorphism C+87T by MicroRNA-107.
Chromogranin A (CHGA) is coreleased with catecholamines from secretory vesicles in adrenal medulla and sympathetic axons. Genetic variation in the CHGA 3'-region has been associated with autonomic control of circulation, hypertension, and hypertensive nephropathy, and the CHGA 3'-untranslated region (3'-UTR) variant C+87T (rs7610) displayed peak associations with these traits in humans. Here, we explored the molecular mechanisms underlying these associations. C+87T occurred in a microRNA-107 (miR-107) motif (match: T>C), and CHGA mRNA expression varied inversely with miR-107 abundance. In cells transfected with chimeric luciferase/CHGA 3'-UTR reporters encoding either the T allele or the C allele, changes in miR-107 expression levels had much greater effects on expression of the T allele. Cotransfection experiments with hsa-miR-107 oligonucleotides and eukaryotic CHGA plasmids produced similar results. Notably, an in vitro CHGA transcription/translation experiment revealed that changes in hsa-miR-107 expression altered expression of the T allele variant only. Mice with targeted ablation of Chga exhibited greater eGFR. Using BAC transgenesis, we created a mouse model with a humanized CHGA locus (T/T genotype at C+87T), in which treatment with a hsa-miR-107 inhibitor yielded prolonged falls in SBP/DBP compared with wild-type mice. We conclude that the CHGA 3'-UTR C+87T disrupts an miR-107 motif, with differential effects on CHGA expression, and that a cis:trans (mRNA:miR) interaction regulates the association of CHGA with BP and hypertensive nephropathy. These results indicate new strategies for probing autonomic circulatory control and ultimately, susceptibility to hypertensive renal sequelae.
Departments of Medicine.
Kuixing
K
Zhang
Departments of Medicine.
Saiful A
SA
Mir
Departments of Medicine.
C Makena
CM
Hightower
Departments of Medicine.
Jose Pablo
JP
Miramontes-Gonzalez
Psychiatry, and.
Adam X
AX
Maihofer
Departments of Medicine.
Yuqing
Y
Chen
Departments of Medicine, Veterans Affairs San Diego Healthcare System, San Diego, California.
Sushil K
SK
Mahata
Psychiatry, and.
Caroline M
CM
Nievergelt
Psychiatry, and.
Nicholas J
NJ
Schork
Department of Internal Medicine, Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, North Carolina; and.
Barry I
BI
Freedman
Departments of Medicine, svaingankar@ucsd.edu.
Sucheta M
SM
Vaingankar
Departments of Medicine, Veterans Affairs San Diego Healthcare System, San Diego, California Institute for Genomic Medicine, University of California at San Diego, La Jolla, California; Pharmacology and.
Daniel T
DT
O'Connor
D020413:3' Untranslated Regions; D000483:Alleles; D000818:Animals; D001794:Blood Pressure; D053379:Chromogranin A / Q000235:genetics* / Q000378:metabolism; D005919:Glomerular Filtration Rate; D057809:HEK293 Cells; D006801:Humans; D006977:Hypertension, Renal / Q000235:genetics* / Q000378:metabolism; D008156:Luciferases; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics*; D016716:PC12 Cells; D011110:Polymorphism, Genetic; D051381:Rats
D020413:3' Untranslated Regions; C506150:CHGA protein, human; D053379:Chromogranin A; C549045:MIRN107 microRNA, human; D035683:MicroRNAs; D008156:Luciferases
CKD; hypertension; molecular genetics; progression of renal failure; systolic BP; transgenic mouse