Dataset Information

Heritable influence of DBH on adrenergic and renal function: twin and disease studies.

ABSTRACT:

Background

Elevated sympathetic activity is associated with kidney dysfunction. Here we used twin pairs to probe heritability of GFR and its genetic covariance with other traits.

Methods

We evaluated renal and adrenergic phenotypes in twins. GFR was estimated by CKD-EPI algorithm. Heritability and genetic covariance of eGFR and associated risk traits were estimated by variance-components. Meta-analysis probed reproducibility of DBH genetic effects. Effect of DBH genetic variation on renal disease was tested in the NIDDK-AASK cohort.

Results

Norepinephrine secretion rose across eGFR tertiles while eGFR fell (p<0.0001). eGFR was heritable, at h(2)?=?67.3±4.7% (p?=?3.0E-18), as were secretion of norepinephrine (h(2)?=?66.5±5.0%, p?=?3.2E-16) and dopamine (h(2)?=?56.5±5.6%, p?=?1.8E-13), and eGFR displayed genetic co-determination (covariance) with norepinephrine (?G?=?-0.557±0.088, p?=?1.11E-08) as well as dopamine (?G?=?-0.223±0.101, p?=?2.3E-02). Since dopamine ?-hydroxylase (DBH) catalyzes conversion of dopamine to norepinephrine, we studied functional variation at DBH; DBH promoter haplotypes predicted transcriptional activity (p<0.001), plasma DBH (p<0.0001) and norepinephrine (p?=?0.0297) secretion; transcriptional activity was inversely (p<0.0001) associated with basal eGFR. Meta-analysis validated DBH haplotype effects on eGFR across 3 samples. In NIDDK-AASK, we established a role for DBH promoter variation in long-term renal decline rate (GFR slope, p?=?0.003).

Conclusions

The heritable GFR trait shares genetic determination with catecholamines, suggesting new pathophysiologic, diagnostic and therapeutic approaches towards disorders of GFR as well as CKD. Adrenergic activity may play a role in progressive renal decline, and genetic variation at DBH may assist in profiling subjects for rational preventive treatment.

SUBMITTER: Pasha DN

PROVIDER: S-EPMC3876991 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Heritable influence of DBH on adrenergic and renal function: twin and disease studies.

Pasha Dalal N DN Davis Jason T JT Rao Fangwen F Chen Yuqing Y Wen Gen G Fung Maple M MM Mahata Manjula M Zhang Kuixing K Trzebinska Danuta D Mustapic Maja M Hightower C Makena CM Lipkowitz Michael S MS Ji Ming M Ziegler Michael G MG Nievergelt Caroline M CM O'Connor Daniel T DT

PloS one 20131231 12

<h4>Background</h4>Elevated sympathetic activity is associated with kidney dysfunction. Here we used twin pairs to probe heritability of GFR and its genetic covariance with other traits.<h4>Methods</h4>We evaluated renal and adrenergic phenotypes in twins. GFR was estimated by CKD-EPI algorithm. Heritability and genetic covariance of eGFR and associated risk traits were estimated by variance-components. Meta-analysis probed reproducibility of DBH genetic effects. Effect of DBH genetic variation ...[more]

PMID: 24391727

Similar Datasets

Project description:IntroductionMesenchymal stem cells (MSCs) play a central role in the remediation of cell and tissue damage. Erythropoietin (EPO) may enhance the beneficial influence of MSCs during recovery from tissue and organ injuries. Microvesicles (MVs) released from MSCs contribute to the restoration of kidney damage. We studied the influence of EPO on MVs derived from MSCs, and the protective effects of these factors in subjects with chronic kidney disease (CKD).MethodsThe MVs derived from untreated MSCs (MSC-MVs) or from MSCs incubated in different concentrations of EPO (1, 10, 100, and 500 IU/ml EPO-MVs) were used to treat renal injury of unilateral ureteral obstruction (UUO) in vivo, and transforming growth factor-β1 (TGF-β1)-induced fibrosis in a human renal proximal tubular epithelial (HK2) cell line in vitro. Western blot and reverse transcription polymerase chain reaction (RT-PCR) analyses were used to evaluate the expression of epithelial and mesenchymal markers in the renal tissue and HK2 cells. Flow cytometry was used to assess apoptosis within the HK2 cells, and microRNA (miRNA) microarray assays were used to determine the expression profiles of miRNA in the MSC-MVs and EPO-MVs.ResultsCompared to MSC-MVs (untreated), there was a significant increase in the number of EPO-MVs derived from MSCs treated with 1-100 IU/ml EPO, and these EPO-MVs had a greater benefit in UUO mice on days 7 and 14. Moreover, the EPO-MVs had a better restorative effect following TGF-β1-induced fibrosis in HK2 cells at 24 h and 48 h. The flow cytometry results revealed that both types of MVs, especially EPO-MVs, play an important anti-apoptotic role in HK2 cells treated with TGF-β1. The miRNA profiles of the MVs revealed that EPO-MVs changed 212 miRNAs (fold-change ≥ 1.5), including miR-299, miR-499, miR-302, and miRNA-200, and that 70.28 % of these changes involved upregulation. The changed miRNA in EPO-MVs may have contributed to their enhanced protective effects following renal injury compared to MSC-MVs.ConclusionsThere was a dose-dependent increase in the level of EPO-MVs within the range of 1-100 IU/ml EPO. Although both MSC-MVs and EPO-MVs protect the kidney from fibrosis-related damage, there is a superior effect of EPO-MVs.

Dataset Information

Heritable influence of DBH on adrenergic and renal function: twin and disease studies.

Background

Methods

Results

Conclusions

Publications

Heritable influence of DBH on adrenergic and renal function: twin and disease studies.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure