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2 cell embryo 24 hours after microinjection of the Sleeping Beauty transposon vector containing green flourescent protein. Sleeping Beauty transposon system successfully allows random integration of a gene of interest into the rat genome.
Hypertension (high blood pressure) is a major risk factor for stroke, heart disease, end organ damage, and contributes to the escalating costs of health care within the United States. Growing evidence supports a role for 20-HETE, a CYP4A metabolite, in the regulation of blood pressure through inhibition of renal ion transport and promotion of the pressure natriuresis response.
Previous data from our laboratory using transfer of Chr 5, containing the CYP4 genes that produce 20-HETE from the Brown-Norway rat onto the Dahl S genetic background in SS.BN5 consomic rats, increases the renal production of 20-HETE, attenuates the development of hypertension, reduces urinary protein excretion, and markedly improves the renal pressure natriuretic response.
Embryos are then implanted into psuedopregnant female rats and 3 or the 8 pups now express our gene of interest. Example is shown using green flourescent protein (GFP).
Based on these data, we hypothesize that increased expression of CYP450 protein and upregulation of the renal formation of 20-HETE will attenuate the rise in mean arterial pressure and progression of renal disease in transgenic Dahl S rats. Toward this end, we have created a transgenic rat utilizing a Sleeping Beauty transposon system, in which the CYP4A1 gene has been inserted into the Dahl S genetic background. Preliminary data using this model suggest a 3-fold increase in renal 20-HETE production and an attenuation of the hypertension in response to a high salt diet (8%NaCl). Through this research we hope to provide new information on the mechanism by which a deficiency in the renal formation of 20-HETE promotes the development of hypertension and renal disease.
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