Molecular Mechanism for Hypertensive Renal Disease

Abstract

Chromogranin A (CHGA) is coreleased with catecholamines from secretory vesicles in adrenal medulla and sympathetic axons. Genetic variation in the CHGA 39-region has been associated with autonomic control of circulation, hypertension, and hypertensive nephropathy, and the CHGA 39-untranslated region (39-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 39-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 39-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.

CircNr1h4 regulates the pathological process of renal injury in salt‐sensitive hypertensive mice by targeting miR‐155‐5p

“…Some studies demonstrate that circRNAs sponge miRNAs with miRNA response elements to sequester miRNAs and subsequently terminate the post-transcriptional control of their target genes. [22][23][24][25][26] MiR-29b, miR-107 and miR-324-3p are involved in the process of hypertensive nephropathy. 20,21 Cumulating evidence has demonstrated that miRNAs play an important role in the regulation of renal development, physiology and pathology.…”

“…12,19 miRNAs are approximately 22-25 nucleotides in length and act as negative regulators of their target mRNAs by promoting mRNA degradation or inhibiting mRNA translation. 25,26 Additionally, miR-214-3p contributes to the development of salt-sensitive hypertension in the kidney. [22][23][24][25][26] MiR-29b, miR-107 and miR-324-3p are involved in the process of hypertensive nephropathy.…”

“…[22][23][24][25][26] MiR-29b, miR-107 and miR-324-3p are involved in the process of hypertensive nephropathy. 25,26 Additionally, miR-214-3p contributes to the development of salt-sensitive hypertension in the kidney. 24 Although these studies demonstrated that miRNAs are involved in the regulation of hypertensive nephropathy, upstream regulators of miRNAs that might be involved in hypertensive kidney injury remain largely unknown.…”

Animal Models of Hypertension: A Scientific Statement From the American Heart Association

“…Alternatively, the use of bacterial artificial chromosomes, which incorporate hundreds of kilobases of DNA, human chromagranin variants have been analyzed in mouse models, for their ability to reduce the risk of hypertension. 76,77 Gene targeting, resulting in loss of gene function, was also achieved initially in the mouse after the development of embryonic stem cells (ESCs). The gene-targeting construct is introduced by transfection or electroporation into ESCs, and those cells that have been correctly targeted by homologous recombination are selected and injected into blastocysts.…”

Comprehensive Bioinformatics Analysis Identifies POLR2I as a Key Gene in the Pathogenesis of Hypertensive Nephropathy

“…These results indicated that HN is possibly a disorder caused by abnormalities in transcription activity and imbalance in redox homeostasis. As previously reported, the abnormal transcription activity of genes (Zhang et al, 2015;Dhande et al, 2020) and oxidative stress (Majzunova et al, 2019;Nguyen et al, 2020) can be a cause or, more often, a potentiating factor for hypertension and hypertensive renal disease. Besides this, three hub genes associated with HN, namely, POLR2L, POLR2G, and POLR2I, were identified by PPI network analysis.…”