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Mutation within the hinge region of the transcription factor Nr2f2 attenuates salt-sensitive hypertension.

ABSTRACT: Genome-wide association studies (GWAS) have prioritized a transcription factor, nuclear receptor 2 family 2 (NR2F2), as being associated with essential hypertension in humans. Here we provide evidence that validates this association and indicates that Nr2f2 is a genetic determinant of blood pressure (BP). Using the zinc-finger nuclease technology, the generation of a targeted Nr2f2-edited rat model is reported. The resulting gene-edited rats have a 15 bp deletion in exon 2 leading to a five-amino-acid deletion in the hinge region of the mutant Nr2f2 protein. Both systolic and diastolic blood pressures of the Nr2f2(mutant) rats are significantly lower than controls. Because the hinge region of Nr2f2 is required for interaction with Friend of Gata2 (Fog2), protein-protein interaction is examined. Interaction of Nr2f2(mutant) protein with Fog2 is greater than that with the wild-type Nr2f2, indicating that the extent of interaction between these two transcription factors critically influences BP.

SUBMITTER: Kumarasamy S

PROVIDER: S-EPMC4486351 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Mutation within the hinge region of the transcription factor Nr2f2 attenuates salt-sensitive hypertension.

Kumarasamy Sivarajan S Waghulde Harshal H Gopalakrishnan Kathirvel K Mell Blair B Morgan Eric E Joe Bina B

Nature communications 20150217

Genome-wide association studies (GWAS) have prioritized a transcription factor, nuclear receptor 2 family 2 (NR2F2), as being associated with essential hypertension in humans. Here we provide evidence that validates this association and indicates that Nr2f2 is a genetic determinant of blood pressure (BP). Using the zinc-finger nuclease technology, the generation of a targeted Nr2f2-edited rat model is reported. The resulting gene-edited rats have a 15 bp deletion in exon 2 leading to a five-amin ...[more]

PMID: 25687237

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Project description:Increased plasma uric acid (hyperuricemia) has been associated with worse outcomes for chronic kidney disease (CKD). But some attempts to control uric acid (UA) in large-cohort clinical trials did not produce clinically meaningful benefits for CKD. Some studies suggest that only hyperuricemia with crystals, but not asymptomatic hyperuricemia promotes the progression of CKD. Salt-sensitivity (SS) in blood pressure is a prevalent trait that is sexually dimorphic and results in kidney damage. But the connection between hyperuricemia and SS hypertension (HTN) is still unclear. Here we tested the connection between the two using both male and female Dahl SS rats, a well-establish model of SS HTN. We hypothesized that mild asymptomatic hyperuricemia is beneficial in controlling the progression of SS HTN. A uricase inhibitor, oxonic acid (2%) (Oxo) was used to induce hyperuricemia and high-salt (HS) (4% NaCl) diet was used to induce SS HTN. After 3 weeks, in response to oxonic acid supplementation, both sexes showed a significant increase of UA in plasma compared to their respective HS-only controls (Males: 0.63 ±0.07 vs. 2.17 ±0.34; Females: 0.78 ±0.15 vs. 2.04 ±0.35 mg/dl, HS vs. HS/oxo). Interestingly, only male HS/oxo rats showed a significant increase in uricosuria (Males: 0.23 ±0.03 vs. 0.45 ±0.06; Femaels: 0.26 ±0.06 vs. 0.26 ±0.001 UA/Cre, HS vs. HS/oxo). Moreover, the mild hyperuricemia was associated with a significant attenuation of the progression and magnitude of the mean arterial pressure in male but not female rats (Males: 157 ±3 vs. 136 ±3; Females: 155 ±6 vs. 154 ±5 mmHg, HS vs. HS/oxo). Xanthine oxidase (XO) is one of the enzymes that produce UA, and its activity has been shown to affect HTN as well. Therefore, we examined the level of XO activity in the plasma after the treatment. While there was no difference in the activity based on the diet within each sex, females had significantly lower levels of XO activity compared to males in each of the diets. To further investigate the beneficial phenotype seen in male rats, we evaluate changes in the progression of renal pathology. The HS/oxo group compared to the HS group had a lower kidney weight/body weight ratio and lower protein cast accumulation, indicating lower kidney damage. Furthermore, the HS/Oxo treated males had less oxidative damage in their tubules than the HS-only males. Bulk-RNA seq done on the male kidneys revealed that attenuated HTN phenotype was associated with an increased expression in Mas1 (MAS receptor), Klk-1 (Kallikrein-1), and Pcsk6 (PCSK6 enzyme) which can all lead to the activation of different vasodilatory pathways. Our study showed that in male but not female Dahl SS rats, asymptomatic mild hyperuricemia accompanied by hyperuricosuria ameliorates the progression of SS HTN and protects kidneys from further damage. Thus, our findings challenge the notion of hyperuricemia being inherently detrimental to health and highlight that this is an oversimplified view of UA’s role in disease.

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Mutation within the hinge region of the transcription factor Nr2f2 attenuates salt-sensitive hypertension.

Publications

Mutation within the hinge region of the transcription factor Nr2f2 attenuates salt-sensitive hypertension.

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