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Varunkumar Pandey-Dissertation.pdf (3.11 MB)

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The Effect of Glucocorticoids on Regulation of the Human Angiotensinogen Gene and Blood Pressure

Pandey, Varunkumar Girijaprasad
http://rave.ohiolink.edu/etdc/view?acc_num=mco1378647891

Abstract Details

2013, Doctor of Philosophy (PhD), University of Toledo, College of Medicine.
Human angiotensinogen gene locus is associated with hypertension. Human angiotensinogen gene (hAGT) has -6A/G polymorphism and -6A (rs5051) allele is associated with increased blood pressure. We have found that hAGT gene has three additional SNPs. Variants -1670A, -1562C, and -1561T almost always occur with -6A haplotype (Hap -6A); and variants -1670G, -1562G, and -1561G almost always occur with -6G haplotype (Hap -6G). We have shown that these polymorphisms affect the binding of glucocorticoid receptor to the promoter. Reporter construct containing 1.8 Kb of the hAGT gene promoter with Hap -6A has 4 fold increased glucocorticoid induced promoter activity as compared to Hap -6G. Therefore, we have generated transgenic (TG) mice containing either Hap -6A or Hap -6G of the hAGT gene to study the regulation of the hAGT gene in an in vivo situation. We have reported that transgenic mice with Hap -6A of hAGT gene has increased plasma angiotensinogen levels and significantly elevated blood pressure as compared to the Hap -6G. Since hAGT is not cleaved by mouse renin, we have generated double transgenic mice with human renin and hAGT gene of either Hap -6A or Hap -6G. We hypothesize that these three additional SNPs in the promoter of Hap -6A may be predisposing to hypertension in response to increased glucocorticoid levels. TG mice with Hap -6A and Hap -6G were treated with dexamethasone (DEX) (10µg/day in drinking water) for 72 hours. Our Q-RTPCR results show that mice with Hap -6A have significant increase in the mRNA expression of hAGT in the liver and the kidney on treatment with DEX whereas no significant changes were observed in Hap -6G. Q-RTPCR results were confirmed by western blots showing significant increase in the DEX induced expression of the hAGT protein in the liver and the kidney of the TG mice with Hap -6A. DEX treatment also increased the plasma hAGT protein and Ang-II levels in TG mice with Hap -6A whereas no significant changes were observed in TG mice with Hap -6G. The systolic blood pressure (SBP) of TG mice containing Hap -6A increased by 12 mmHg on treatment with DEX as compared to 5mmHg in the mice with Hap -6G. We subjected these TG mice to increased dosage of DEX at 50µg/day and observed a dose dependent modulation of SBP. DEX dependent increase in the SBP was reduced by losartan.
Ashok Kumar, PhD (Committee Chair)
Bina Joe, PhD (Committee Member)
Andrew Beavis, PhD (Committee Member)
Nitin Puri, MD PhD (Committee Member)
Zahoor Shah, PhD (Committee Member)
121 p.
Biochemistry; Genetics; Molecular Biology; Pharmacology; Physiology
Human; Renin-Angiotensin system; Angiotensinogen; Hypertension; Genetics; Single Nucleotide Polymorphisms; Transgenic mice

Recommended Citations

Citations

  • Pandey, V. G. (2013). The Effect of Glucocorticoids on Regulation of the Human Angiotensinogen Gene and Blood Pressure [Doctoral dissertation, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=mco1378647891

    APA Style (7th edition)

  • Pandey, Varunkumar. The Effect of Glucocorticoids on Regulation of the Human Angiotensinogen Gene and Blood Pressure. 2013. University of Toledo, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=mco1378647891.

    MLA Style (8th edition)

  • Pandey, Varunkumar. "The Effect of Glucocorticoids on Regulation of the Human Angiotensinogen Gene and Blood Pressure." Doctoral dissertation, University of Toledo, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=mco1378647891

    Chicago Manual of Style (17th edition)

mco1378647891
762
© 2013, all rights reserved.
This open access ETD is published by University of Toledo Health Science Campus and OhioLINK.
Release 3.2.12