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The extent to which a reduced nephron endowment contributes to hypertension and renal disease is confounded in models created by intrauterine insults that also demonstrate other phenotypes. Furthermore, recent data suggest that a reduced nephron endowment provides the 'first hit' and simply increases the susceptibility to injurious stimuli. Thus we examined nephron number, glomerular volume, conscious mean arterial pressure (MAP), and renal function in a genetic model of reduced nephron endowment before and after a high-salt (5%) diet. One-yr-old glial cell line-derived neurotrophic factor wild-type (WT) mice, heterozygous (HET) mice born with two kidneys (HET2K), and HET mice born with one kidney (HET1K) were used. Nephron number was 25% lower in HET2K and 65% lower in HET1K than WT mice. Glomeruli hypertrophied in both HET groups by 33%, resulting in total glomerular volumes that were similar between HET2K and WT mice but remained 50% lower in HET1K mice. On a normal-salt diet, 24-h MAP was not different between WT, HET2K, and HET1K mice (102 [+ or -] 1, 103 [+ or -] 1, and 102 [+ or -] 2 mmHg). On a high-salt diet, MAP increased 9.1 [+ or -] 1.9 mmHg in HET1K mice (P < 0.05) and 5.4 [+ or -] 0.9 mmHg in HET2K mice (P < 0.05) and did not change significantly in WT mice. Creatinine clearance was 60% higher in WT mice but 30% lower in HET2K and HET1K mice fed a high-salt diet than in controls maintained on a normal-salt diet. Thus a reduction in nephron number (or total glomerular volume) alone does not lead to hypertension or kidney disease in aged mice, but exposure to high salt uncovers a hypertensive and renal phenotype. nephron number; congenital nephron deficit; hypertension; unilateral renal agenesis; salt sensitivity doi: 10.1152/aj prenal.00049.2010.

McArdle AM, Roberts CT, Maduwegedera D, Flower RL, Denton KM. Chronic maternal hypertension characterized by renal dysfunction is associated with reduced placental blood flow during late gestation in rabbits. Am J Physiol Regul lntegr Comp Physiol 298: R1043-R1049, 2010. First published January 20, 2010; doi: 10.1152/ajpregu.00202.2009.--Maternal hypertension associated with renal disease is a common pregnancy complication. Previously, we have shown in a rabbit model of mild hypertension that offspring from hypertensive mothers have increased blood pressure as adults, In human pregnancy, hypertension has been associated with decreased utero-placental blood flow. The aim of this study was to determine placental blood flow (PBF) in mild (2-kidney-l-wrapped; 2K-IW) and moderate (2-kidney-2-wrapped; 2K-2W) rabbit models of maternal hypertension. We hypothesized that PBF would be inversely related to the severity of the hypertension. PBF and renal blood flow (RBF) were measured using microspheres on day 28 of a 32-day gestation, in normotensive (sham), 2K-1W, and 2K-2W hypertensive groups. Mean arterial pressure (MAP, ~7 mmHg, P < 0.05) was increased, and RBF (~35%, P < 0.05) was reduced in the 2K-1W and 2K-2W (MAP ~20 mmHg, P < 0.01; RBF ~53%, P < 0.05) groups compared with the sham group. In the 2K-1W group, PBF fell by ~12% (P = 0.08) and fetal-toplacental weight ratio increased by ~12% (P < 0.01) compared with the sham group, reflecting an increase in the functional capacity of the placenta to deliver nutrients to the fetus. In the 2K-2W group, PBF decreased ~51% (P < 0.05) compared with the sham group, without changes in placental efficiency. Thus, in late gestation, placental blood flow was significantly reduced in the moderate hypertension group, without accompanying changes in fetal or placental weight or placental efficiency. In contrast, mild hypertension resulted in an increase in placental efficiency, without significant changes in placental blood flow. These findings suggest that mild and moderate hypertension may alter placental delivery of nutrients via differing mechanisms dependent upon the severity of the hypertension. placental blood flow; rabbit; hypertension; renal blood flow doi: 10.1152/ajpregu.00202.2009.

We examined whether deficits in glomerular capillary surface area associated with a congenital nephron deficit could be corrected by glomerular hypertrophy. Using unbiased stereological techniques, we examined the time course and mode of glomerular hypertrophy in mice lacking one allele for glial cell line-derived neurotrophic factor (GDNF). These GDNF heterozygous (Het) mice are born with ~30% less nephrons than wild-type (WT) littermates. An additional group of GDNF Het mice received the angiotensin type 1 ([AT.sub.1])-receptor antagonist candesartan (Cand; 10 mg x [kg.sup.-1] x [day.sup.-1]) from 5 wk of age to determine the role of [AT.sub.1] receptors in the compensatory hypertrophy. At 10 wk of age, the total volume of renal corpuscles, glomerular capillary surface area, and length of glomerular capillaries in the kidneys of GDNF Het mice were all markedly (~45%) less than that of WT mice (P < 0.001). However, by 30 wk, and persisting at 60 wk of age, GDNF Het and WT mice did not significantly differ in any of these parameters. Furthermore, conscious 24-h mean arterial pressure (MAP) did not differ between GDNF Het and WT mice at any time point. MAP of GDNF Het-Cand mice was 20-30 mmHg less than that of GDNF Het-vehicle mice at all three ages, but Cand treatment did not significantly alter glomerular capillary dimensions. In conclusion, we have demonstrated that the deficit in glomerular capillary surface area associated with a congenital nephron deficit can be corrected for in adulthood by an increase in the total length of glomerular capillaries. This process does not require [AT.sub.1] receptor activation. 24-hour blood pressure; nephron endowment; kidney; glomerular capillary surface area; stereology; glomerular hypertrophy

The risk of developing many adult-onset diseases, including hypertension, type 2 diabetes, and renal disease, is increased in low-birth-weight individuals. A potential underlying mechanism contributing to the onset of these diseases is the formation of a low nephron endowment during development. Evidence from the human, as well as many experimental animal models, has shown a strong association between low birth weight and a reduced nephron endowment. However, other animal models, particularly those in which the mother is exposed to elevated glucocorticoids for a short period, have shown a 20-40% reduction in nephron endowment without discernible changes in the birth weight of offspring. Such findings emphasize that a low birth weight is one, but certainly not the only, predictor of nephron endowment and suggests reduced nephron endowment and risk of developing adult-onset disease, even among normal-birth-weight individuals. Recognition of the dissociation between birth weight and nephron endowment is important for future studies aimed at elucidating the role of a reduced nephron endowment in the developmental programming of adult disease. glucocorticoid exposure; kidney development; hypertension

The aim of this study was to determine the contribution of neuropeptide Y (NPY) [Y.sub.1] receptors in neurally mediated reductions in renal medullary perfusion. In pentobarbital sodium-anesthetized rabbits, electrical stimulation of the renal nerves (RNS, 0.5-16 Hz) decreased renal perfusion in a frequency-dependent manner. Under control conditions, 4 Hz reduced cortical and medullary perfusion by -85 [+ or -] 3% and -43 [+ or -] 7%, whereas 8 Hz reduced them by -93 [+ or -] 2% and -73 [+ or -] 4%, respectively. After [Y.sub.1] receptor antagonism with BIBO3304TF (0.1 mg/kg plus 0.2 mg*[kg*.sup.-1][h.sup.-1]), RNS reduced perfusion less (by -65 [+ or -] 9% and -12 [+ or -] 8% at 4 Hz). [[alpha].sub.1]-Adrenoceptor antagonism with prazosin (0.2 mg/kg plus 0.2 mg [kg.sup.-1][h.sup.-1]) also inhibited RNS-induced reductions in renal perfusion (-80 [+ or -] 4% and -37 [+ or -] 10% reductions in the cortex and medulla, respectively, at 8 Hz). When given after BIBO3304TF treatment, prazosin inhibited RNS-induced reductions in cortical and medullary perfusion more profoundly (-57 [+ or -] 12% and -25 [+ or -] 9% reductions, respectively, at 8 Hz). [Y.sub.1] receptor- and [[alpha].sub.1]-adrenoceptor-blockade were confirmed by testing vascular responses to renal arterial NPY and phenylephrine boluses. NPY-positive immunolabeling was observed around interlobular arteries, afferent and efferent arterioles, and in the outer medulla. In conclusion, [Y.sub.1] receptors and [[alpha].sub.1]-adrenoceptors contribute to RNS-induced vasoconstriction in the vessels that control both cortical and medullary perfusion. Consistent with this, NPY immunostaining was associated with blood vessels that control perfusion in both regions. There also seems to be an interaction between [Y.sub.1] receptors and [[alpha].sub.1]-adrenoceptor-mediated neurotransmission in the control of renal perfusion. renal medullary blood flow; sympathetic nervous system; BIBO3304TF

Predominant postglomerular vascular resistance response to reflex renal sympathetic nerve activation during ANG II clamp in rabbits. Am J Phvsiol Regul Integr Comp Physiol 287: R780-R786, 2004. First published June 10, 2004; 10.1152/ ajpregu.00202.2004.--We have shown previously that a moderate reflex increase in renal sympathetic nerve activity (RSNA) elevated glomerular capillary pressure, whereas a more severe increase in RSNA decreased glomerular capillary pressure. This suggested that the nerves innervating the glomerular afferent and efferent arterioles could be selectively activated, allowing differential control of glomerular capillary pressure. A caveat to this conclusion was that intrarenal actions of neurally stimulated ANG II might have contributed to the increase in postglomerular resistance. This has now been investigated. Anesthetized rabbits were prepared for renal micropuncture and RSNA recording. One group (ANG II clamp) received an infusion of an angiotensin-converting enzyme inhibitor (enalaprilat, 2 mg/kg bolus plus 2 mg*[kg.sup.-1]*[h.sup.-1]) plus ANG II (~20 ng*[kg.sup.-1]*[min.sup.-1]), the other vehicle. Measurements were made before (room air) and during 14% [O.sub.2]. Renal blood flow decreased less during ANG II clamp compared with vehicle [9 [+ or -] I% vs. 20 [+ or -] 4%, interaction term ([P.sub.GT]) < 0.051, despite a similar increase in RSNA in response to 14% [O.sub.2] in the two groups. Arterial pressure and glomerular filtration rate were unaffected by 14% [O.sub.2] in both groups. Glomerular capillary pressure increased from 33 [+ or -] 1 to 37 [+ or -] 1 mmHg during ANG II clamp and from 33 [+ or -] 2 to 35 [+ or -] 1 mmHg in the vehicle group before and during 14% [O.sub.2], respectively ([P.sub.GT] < 0.05). During ANG II clamp, postglomerular vascular resistance was still increased in response to RSNA during 14% [O.sub.2], demonstrating that the action of the renal nerves on the postglomerular vasculature was independent of the renin-angiotensin system. This further supports our hypothesis that increases in RSNA can selectively control pre- and postglomerular vascular resistance and therefore glomerular ultrafiltration. kidney: renal innervation; glomerular capillary pressure: renal micropuncture: hypoxia

Recently, we designed a group of peptides by sequential substitution of the naturally occurring α-amino acid throughout the Ang III peptide sequence with the corresponding β-amino acid. β-Amino acid substitution at the proline residue of Ang III (β-Pro7-Ang III) resulted in a highly selective AT2R ligand, demonstrating remarkable selectivity for the AT2R in both binding and functional studies. To provide additional functional evidence for the suitability of β-Pro7 Ang III as a novel AT2R agonist, we tested effects of acute systemic administration of β-Pro7-Ang III on renal hemodynamic and excretory function in anesthetized normotensive male and female rats. We also compared the natriuretic effects of acute intrarenal administration of native Ang III and β-Pro7-Ang III in the presence of systemic AT1R blockade in anesthetized female rats to allow for the differentiation of systemic versus direct intrarenal natriuretic actions of β-Pro7-Ang III. In both male and female rats, acute systemic administration of β-Pro7-Ang III elicited renal vasodilatation and natriuresis. Notably, greater renal vasodilatory effects were observed in female versus male rats at the highest dose of β-Pro7-Ang III administered. Moreover, intra-renal administration of β-Pro7-Ang III produced significant natriuretic effects in female rats and, like Ang III, evoked AT2R translocation to the apical plasma membrane in renal proximal tubular cells. Taken together, our findings support the use of β-Pro7-Ang III as a novel AT2R agonist and experimental tool for exploring AT2R function and its potential as a therapeutic target. Furthermore, our findings provide further evidence of a sex-specific influence of AT2R stimulation on renal function. [ABSTRACT FROM AUTHOR]