Fetal uninephrectomy in male sheep alters the systemic and renal responses to angiotensin II infusion and AT1R blockade

Abstract

Fetal uninephrectomy (uni-x) at 100 days of gestation results in compensatory nephrogenesis in the remaining kidney, resulting in a 30% reduction in total nephron number in male sheep. Recently, we showed that uni-x males at 6 mo of age have elevated arterial pressure, reduced renal blood flow (RBF), glomerular filtration rate (GFR), and low plasma renin levels (Singh R, Denton K, Bertram J, Jefferies A, Head G, Lombardo P, Schneider-Kolsky M, Moritz K. J Hypertens 27: 386-396, 2009; Singh R, Denton K, Jefferies A, Bertram J, Moritz K. Clin Sci (Lond) 118: 669-680, 2010). We hypothesized this was due to upregulation of the intrarenal renin-angiotensin system (RAS). In this study, renal responses to ANG II infusion and ANG II type 1 receptor (AT1R) blockade were examined in the same 6-mo-old male sheep. Uni-x animals had reduced levels of renal tissue and plasma renin and ANG II. Renal gene expression of renin, and gene and protein levels of AT1R and AT2R, were significantly lower in uni-x animals. In response to graded ANG II infusion, sham animals had the expected decrease in conscious RBF and GFR. Interestingly, the response was biphasic in uni-x sheep, with GFR initially decreasing, but then increasing at higher ANG II doses (34 ± 7%; P(group × treatment) < 0.001), due to a paradoxical decrease in renal vascular resistance (P(group × treatment) < 0.001). In response to AT1R blockade, while GFR and RBF responded similarly between groups, there was a marked increase in sodium excretion in uni-x compared with sham sheep (209 ± 35 vs. 25 ± 12%; P < 0.001). In conclusion, in 6-mo-old male sheep born with a single kidney, these studies demonstrate that this is a low-renin form of hypertension, in which responses to ANG II are perturbed and the intrarenal RAS is downregulated.

Renal responses to furosemide are significantly attenuated in male sheep at 6 months of age following fetal uninephrectomy

“…We have also recently reported that basal plasma renin and ANG II and renal tissue renin and ANG II levels are significantly reduced in 6-mo-old uni-x male sheep as are levels of both ANG II receptors (AT1R and AT2R) (33). Additionally, we showed that in response to increases in arterial pressure induced by exogenous ANG II infusion, uni-x male sheep exhibited a paradoxical increase in GFR, suggesting the renal autoregulatory mechanisms that usually buffer the kidney against fluctuations in arterial pressure were perturbed in these uni-x animals (33).…”

“…We have previously reported that fetal uni-x in male sheep results in an approximate 30% reduction in nephron number at the completion of nephrogenesis due to compensatory nephrogenesis in the remaining kidney (15). Male uni-x sheep have low plasma renin levels, elevated arterial pressure, and reduced glomerular filtration rate (GFR) and renal blood flow at 6 mo of age (15,(31)(32)(33).…”

“…Furthermore, despite the delay in onset of sodium and water excretion in response to acute volume expansion, both diuresis and natriuresis were significantly exaggerated in the uni-x animals resulting in greater water and sodium loss than control animals (32) further indicating that the tight regulation of sodium homeostasis is impaired in the uni-x sheep, which could indicate a rightward resetting of the tubuloglomerular feedback (TGF) response. Very recently we have shown that renal responses to exogenous angiotensin II (ANG II) infusion are significantly altered in the uni-x animals, with a reduction in GFR occurring at low-dose ANG II but an increase in GFR occurring at higher doses of ANG II when maximal increases in arterial pressure were observed, suggesting an impairment in renal autoregulation (33). The response to ANG II in conjunction with the response to volume expansion in the uni-x sheep suggested to us that the supposed impairment in renal autoregulation in response to ANG II may be associated with a rightward resetting of the TGF response.…”

Variable responses of regional renal oxygenation and perfusion to vasoactive agents in awake sheep

“…This could arise if ANG II were to increase sodium reabsorption, or to reduce the efficiency of oxygen utilization for sodium reabsorption in the medullary thick ascending limbs and/or the distal nephron. Such effects are likely, given that 1) glomerular filtration rate is better maintained than RBF during infusion of ANG II in conscious sheep (27) and 2) ANG II stimulates superoxide production and thus sodium reabsorption in the thick ascending limb (22). On the other hand captopril increased RBF and renal oxygen consumption, but despite this hyperemia there were no significant changes in cortical or medullary LDF or tPO 2 .…”

Transgenerational programming of fetal nephron deficits and sex-specific adult hypertension in rats

“…In F2 Control and Restricted rats studied to 6 months, renin activity, angiotensin II (AngII) and angiotensin 1-7 (Ang1-7) content were analysed in plasma in frozen renal cortices using radioimmunoassay techniques (Prosearch International, Malvern, Vic., Australia; Singh et al 2011).…”