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Mechanisms underlying the perturbations in cardiovascular and renal function in 5-year old female sheep following fetal uninephrectomy
thesisposted on 28.02.2017, 00:33 by Lankadeva, Yugeesh Ryan
Background: A congenital nephron deficit has been strongly implicated in the development of hypertension in adult life in humans and a variety of animal models. Using an ovine model of fetal uninephrectomy (uni-x), we have demonstrated that female uni-x sheep with intact ovaries develop hypertension by 2 years of age. Despite no overt exacerbation in hypertension or a further decline in glomerular filtration rate (GFR), these intact female uni-x sheep demonstrated greater reductions in renal blood flow (RBF) by 5 years of age. Aims: The aim of my studies was to examine the mechanisms underlying the perturbations in renal function in a cohort of 5-year old female uni-x sheep. Methods: Cardiovascular and renal responses to an acute saline load (2.5% body weight) during vehicle and furosemide (0.5 mg/kg bolus + 1 mg/kg/h, i.v) infusion, and to systemic nitric oxide (NO) inhibition (L-NAME, bolus 40mg/kg + 20mg/kg/h i.v.) were examined in conscious sham (n=7) and uni-x (n=7) sheep. Vascular reactivity was assessed in isolated renal arteries and in several other resistance arteries from sham (n=9) and uni-x (n=8) sheep. Results: Female uni-x sheep at 5 years of age exhibited an impaired ability to excrete an acute saline load, revealing not only reductions in the filtered load of sodium, but also alterations in tubular sodium reabsorption and reductions in the contribution of the renin angiotensin system (RAS) (Chapter 3). The effect of furosemide to increase RBF and GFR basally, as well as, abolish renal hemodynamic and PRA responses to a saline load observed in the sham animals, were all but absent in the uni-x sheep, suggesting that tubuloglomerular feedback (TGF) had been reset to a lower sensitivity. Furthermore, cyclooxygenase-2 (COX-2) expression was down-regulated within the renal cortex in uni-x sheep. Reduction in COX-2 derived prostaglandins, especially within the macula densa, could contribute to the reduced gain of the RAS, which may in turn, desensitize TGF in uni-x sheep (Chapter 4). Female uni-x sheep at 5 years of age demonstrated a reduced contribution of NO to the modulation of renal hemodynamics and sodium excretion. Moreover, the reduction in resting RBF and GFR in uni-x sheep was associated with renal vascular dysfunction, consisting of impaired basal NO production/bioavailability, endothelial dysfunction and enhanced smooth muscle responsiveness to vasoconstrictors and sympathetic nerve stimulation (Chapter 5). Conclusion: These findings highlight pivotal mechanisms underlying the perturbations in both cardiovascular and renal function, which may represent a vital link to the development and maintenance of hypertension in 5-year old female sheep born with a nephron deficit.